Polymers and nanogel materials and methods for making and using the same

ABSTRACT

Provided are articles such as medical devices which comprise at least one water soluble, crosslinked copolymer. The primary polymer chains of the copolymer are hydrophilic and independently have a degree of polymerization in the range of about 10 to about 10,000. The water soluble, crosslinked copolymers of the present invention are free from terminal substrate associating segments. The copolymers may be incorporated into a formulation from which the article is made or may be contacted with the article post-formation.

RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.13/899,694 filed May 22, 2013; currently pending, which claims priorityto U.S. Provisional Patent Application No. 61/651,767, filed on May 25,2012, entitled “POLYMERS AND NANOGEL MATERIALS AND METHODS FOR MAKINGAND USING THE SAME”; and U.S. Provisional Patent Application No.61/771,961, filed on Mar. 4, 2013, entitled “POLYMERS AND NANOGELMATERIALS AND METHODS FOR MAKING AND USING THE SAME,” the contents ofwhich are incorporated by reference.

TECHNICAL FIELD

The present invention relates to copolymers that are cross-linked butnot macroscopically gelled. The copolymers do not have separate terminalsegments which can associate with a polymeric substrate. Such copolymerscan be amphiphilic or hydrophilic. Nanogel materials are also provided.These copolymers and nanogel materials may be incorporated into avariety of substrates, including medical devices, to improve thewettability and lubricity and inhibit protein and/or lipid uptakethereof.

BACKGROUND

Contact lenses have been used commercially to improve vision since the1950s. The first contact lenses were made of hard materials. Althoughthese lenses are currently used, they are not widely used due to theirpoor initial comfort and their relatively low permeability to oxygen.Later developments in the field gave rise to soft contact lenses, basedupon hydrogels. Many users find soft lenses are more comfortable, andincreased comfort levels allow soft contact lens users to wear theirlenses for longer hours than users of hard contact lenses.

Another class of available contact lenses is silicone hydrogel contactlenses. Silicone-containing components are combined with conventionalhydrogel components to form silicone hydrogels which display increasedoxygen permeability compared to conventional hydrogels. However, somesilicone hydrogels display undesirably high contact angles and proteinuptake compared to conventional hydrogel lenses.

Various compounds have been disclosed as suitable for treating preformedsilicone hydrogel contact lenses including surface active segmentedblock copolymers, substantially water-soluble silicone-containingsurfactants, functionalized hybrid PDMS/polar amphipathic copolymerblock systems, including polydimethylsiloxane-PVP block copolymers and(meth)acrylated polyvinylpyrrolidone. U.S. Patent Appln. Ser. No.2011/0275734 is directed to “non-reactive, hydrophilic polymers havingterminal siloxanes,” which have linear or branched hydrophilic segments.There remains a need for methods for improving the properties of contactlenses and particularly silicone hydrogel contact lenses.

SUMMARY OF THE INVENTION

The present invention relates to compositions comprising, consisting andconsisting essentially of at least one hydrophilic nanogel materialcomprising, consisting and consisting essentially of one or morecross-linked copolymers, wherein said copolymer comprises, consists andconsists essentially of one or more primary polymer chain having adegree of polymerization in the range of about 10 to about 10,000, andwherein said hydrophilic nanogel material (a) associates, with a surfaceand (b) is free from terminal substrate associating segments.

The present invention further relates to ophthalmic devices comprising,consisting and consisting essentially of at least onesilicone-containing polymer and at least one water soluble, cross-linkedcopolymer comprising, consisting and consisting essentially of aplurality of primary polymer chains each having a degree ofpolymerization in the range of about 10 to about 10,000, wherein saidcopolymer is associated with at least one surface of said ophthalmicdevice and provides said ophthalmic device with a reduction in lipiduptake compared to the silicone-containing polymer of at least about20%.

The present invention relates to a process comprising, consisting andconsisting essentially of contacting a contact lens with a solutioncomprising, consisting and consisting essentially of a lipid uptakereducing amount of at least one water soluble, crosslinked copolymerunder contacting conditions suitable to associate said copolymer withsaid contact lens; wherein said cross-linked copolymer comprises,consists and consists essentially of a plurality of crosslinked primarypolymer chains each having a degree of polymerization in the range ofabout 10 to about 10,000, wherein said crosslinked copolymer does notcomprise repeating units comprising a carboxylic acid group bondeddirectly to the polymer backbone. The present invention further relatedto a process comprising, consisting and consisting essentially of:forming a reaction mixture comprising at least one hydrophiliccomponent, at least and at least one water soluble, cross-linkedcopolymer comprising, consisting and consisting essentially of aplurality of primary polymer chains each having a degree ofpolymerization in the range of about 10 to about 10,000, and curing saidreaction mixture to form a contact lens. The compositions of the presentinvention comprising, consisting and consisting essentially of watersoluble, crosslinked polymers having primary chains, represented by theformula

wherein R₁ is a divalent group selected from the group consisting ofoptionally substituted alkylene; optionally substituted saturated,unsaturated or aromatic carbocyclic or heterocyclic rings; optionallysubstituted alkylthio; optionally substituted alkoxy; or optionallysubstituted dialkylamino;U is independently selected from the group consisting of hydrogen,halogen, C₁-C₄ alkyl which may be optionally substituted with hydroxyl,alkoxy, aryloxy (OR″), carboxy, acyloxy, aroyloxy (O₂CR″),alkoxy-carbonyl, aryloxy-carbonyl (CO₂R″) and combinations thereof.V is independently selected from the group consisting of R″, —CO₂R″,—COR″, —CN, —CONH₂, —CONHR″, —CONR″₂, —O₂CR″, —OR″, cyclic and acyclicN-vinyl amides and combinations thereof;R″ is independently selected from the group consisting of optionallysubstituted C₁-C₁₈ alkyl, C₂-C₁₈ alkenyl, aryl, heterocyclyl, alkarylwherein the substituents are independently selected from the group thatconsists of epoxy, hydroxyl, alkoxy, acyl, acyloxy, carboxy,carboxylate, sulfonic acid, and sulfonate, alkoxy- or aryloxy-carbonyl,isocyanato, cyano, silyl, halo, dialkylamino; phosphoric acids,phosphates, phosphonic acids, phosphonates and combinations thereof;R₁₅′ and R₁₅ are residues of hydrophilic, free radical reactivecross-linking agents;R₁₈ is a controlled radical polymerization agent and in some embodimentsR₂₄ is selected from the group consisting of monovalent RAFT agents,ATRP agents, TERP agents and NMP agents;ζ_(i) is another primary chain, are mole fractions, and a is equal toabout 0.85 to about 0.999, β is not 0, and the mole fractions of β and γcombined are about 0.15 to about 0.001.In another embodiment the compositions of the present inventioncomprise, consist and consist essentially of water soluble, crosslinkedpolymers having primary chains, ζ, represented by the formula

Wherein R₁, U, V, R₁₅, R₁₅′, α, β, γ and m are as defined above.

The compositions impart excellent wettability and lubricity along withreduced protein and/or lipid update, and polymeric articles associatedwith the same. Methods of making and using these compositions are alsodisclosed. Compositions comprise semi-crosslinked, ungelled copolymerwhich may be crosslinked after formation of the polymer chains, or maybe derived from copolymerization of at least one ethylenicallyunsaturated monomer with a poly-functional ethylenically unsaturatedmonomer. Such copolymers can be used as nanogel compositions thatcontain at least one stable, block copolymer that is cross-linked butnot macroscopically gelled. The copolymers when preformed prior tocrosslinking have a degree of polymerization of in the range of about 10to about 10,000. The copolymers of the present application may beincluded in the reactive mixture from which the ophthalmic device ismade, or may be associated with ophthalmic device after the ophthalmicdevice is formed. Incorporation of at least one copolymer of the presentinvention on or in the ophthalmic device provides an improvement in atleast one property of said ophthalmic device, such as a reduction inlipid uptake compared to only the substrate, of at least about 20%. Thecopolymers can be can be amphiphilic or hydrophilic.

Also provided are methods of inhibiting or reducing lipid uptake by acontact lenses, the methods comprising contacting the contact lenseswith a solution comprising at least one water soluble, crosslinkedcopolymer having a degree of polymerization of about 10 to about 10,000,under conditions to entrap or associate said water soluble, crosslinkedcopolymer with said contact lens.

DESCRIPTION OF THE DRAWINGS

The FIGURE is a graph of the molecular weight vs. lipid uptake forsenofilcon A lenses treated with PVP-Siloxane copolymers.

DETAILED DESCRIPTION

Before describing several exemplary embodiments of the invention, it isto be understood that the invention is not limited to the details ofconstruction or process steps set forth in the following description.The invention is capable of other embodiments and of being practiced orbeing carried out in various ways.

It has been found that despite advances made by the use of previouslydeveloped non-reactive, hydrophilic polymers having terminal siloxanes,which have linear, branched or combed hydrophilic segments, in reducinglipid and/or protein uptake and enhancing lubricity and wettability ofcontact lenses, a limit on improved properties is reached as molecularweight increases. The FIGURE depicts this limit with respect tomolecular weight. From the plot in the FIGURE, it is apparent that forsenofilcon A lenses treated with PVP-Siloxane copolymers with increasingmolecular weights, the lipid uptake decreases to a minimal level ofabout 15 μg/lens when the hydrophilic PVP segment reaches a molecularweight of about 80 kDa. For lenses treated with PVP-Siloxane copolymerswith molecular weights above 80 kDa, no additional reduction in lipiduptake on senofilcon A is observed.

Surprisingly, it has been found that polymer nanogels havingcross-linked or “bridged” hydrophilic segments, without separatesubstrate associating segments can lead to contact lenses with improvedproperties, for example, reduced lipid and protein update as well aslower friction. Also, it is thought that choice of cross-linking agentand degree of cross-linking can be tailored according to desiredapplications and specific substrate material.

As used herein “associated” means that the copolymer is retained in oron the substrate without covalent bonding. Associated may includephysical retention, such as entanglement or anchoring, or hydrogenbonding, van der Waals forces, dipole-dipole interactions, electrostaticattraction, and combinations of these effects. It has been surprisinglyfound that the association between the semi-crosslinked block copolymersand the substrate is persistent, and is maintained even with digitalrubbing. When the substrate is a contact lens, the semi-crosslinkedblock copolymers are retained in and/or on the contact lenses throughthe desired wear cycle, including in embodiments where the contact lensis a reusable lens, through cleaning with a digital rub.

As used herein “associative segment” means a portion of the terminalsegment of the polymer that is retained or associated in or on asurface, region, or segment of a substrate. An associative segment canbe hydrophilic or hydrophobic.

As used herein “non-reactive” means the WSC polymer lacks functionalgroups which form covalent bonds under the reaction, storage and useconditions. For example, when the hydrophilic polymer is contacted witha substrate such as a contact lens before autoclaving, very few (lessthan 1 wt %) of the WSC polymers contain residual reactive groups. Evenif residual groups were present, the contacting conditions lack theinitiators necessary to catalyze free radical reactions. Thus, the WSCis incapable of forming covalent bonds with the substrate. It will beappreciated by those of skill in the art that while a very small numberof WSC polymer (less than 5 wt %, and less than 1 wt %) may have aresidual reactive group, there are too few residual reactive groups toassociate desirable or functional amounts of the crosslinked nanogelwith the substrate. The vastly predominating effect keeping the WSCpolymer associated with the substrate is entrapment of at least aportion of the WSC polymer.

The term “cross-linked” refers to the attachment of a polymer chain toone or more polymer chain(s) via a bridge or multiple bridges, composedof either an element, a group or a compound, that join certain carbonatoms of the chains by primary bonds, including covalent, ionic andhydrogen bonds. In various embodiments of the invention disclosedherein, cross-linking may occur via covalent bonding, ionic bonding,hydrogen bonding, or the like. An exemplary embodiment of covalentcross-linking would include the in situ formation of cross-links duringa free-radical copolymerization of a mono-vinyl monomer and monomercontaining multiple (i.e. 2 or more) vinyl substituents. Such apolymerization would result in the covalent cross-linking of multiplepolymer chains to each other and (depending on the extent of monomerconversion and molar quantity of the cross-linker) the formation of amacroscopic gel.

Ionic cross-linking of polymer chains may occur in situ (i.e. duringpolymerization) or post-polymerization. The latter case may occur whenan aqueous solution containing a polymeric cationic material is added toan aqueous solution containing a polymeric anionic material. Uponmixture of the two ionic polymers, polymer-polymer complexation alongwith small-counter-ion liberation occurs, leading to the formation ofionically cross-linked polymer-polymer complexes. The solubility of suchcomplexes is predominately governed by the stoichiometry of positive andnegative charge. Formation of such ionic cross-links between polyanionicand polycationic materials in solution is well known to those skilled inthe art. The former case of ionic cross-linking may occur when amono-vinyl monomer is copolymerized with a di-vinyl cross-linker that iscomposed of two ethylenically unsaturated monomers which are connectedto each other via an ionic bond. Such “ionic cross-linkers” may beformed by combining an ethylenically unsaturated monomer containing anacidic (e.g. a carboxylic acid) moiety with an ethylenically unsaturatedmonomer containing a basic moiety (e.g. a tertiary amine) through simpleacid/base chemistry to form a monomer-monomer complex or divinylcovalent organic salt.

In the context of the disclosed invention, cross-linking via hydrogenbonding may occur when a polymer with multiple proton-donating moietiesis combined in solution with a polymer with multiple proton-acceptingmoieties. In such embodiments, the two polymers are able to form solubleor insoluble complexes, depending on the ratio of proton-donating groupsto proton-accepting groups in the complex, as well as the abundance ofadditional solubilizing or non-solubilizing moieties present on thepolymer chains.

As used herein “nanogel” means submicron hydrogel particles which aresoluble or indefinitely dispersible at room temperature in aqueoussolutions. The solubility of a solution may be confirmed by making a 1wt % of the crosslinked nanogel in water and filtering the solutionthrough a 0.45 micron nylon syringe filter, such as those available fromWhatman or Pall Membranes. Aqueous solutions (2 and in some cases 5 wt%) may be desirable. Solutions which are soluble will maintain at leastabout 90% and in some embodiments at least about 95%, 99% of saidnanogel in solution. In one or more embodiments, the solutions areclear. In one embodiment the aqueous solution is at least about 50weight % water or lens packing solution, in some embodiments at leastabout 70 weight %, in other embodiments at least about 90 weight %, inother embodiments least about 99 weight %, and in other embodimentsleast about 99.5 weight %.

The water soluble, crosslinked (WSC) polymers or nanogels are in amacroscopically ungelled state, making them soluble in aqueoussolutions, including ophthalmic solutions and compositions. The WSCpolymers are generally in an ungelled state at the temperature at whichthey are associated or incorporated into the ophthalmic solution orcomposition. For ophthalmic devices such as contact lenses, it may notbe necessary for the WSC polymer to be ungelled once it is incorporatedor associated with the contact lens. However, for ophthalmic solutions,the WSC polymer generally remains ungelled throughout storage, and insome embodiments, use. Small quantities of gelled polymer (less thanabout 5 wt %) may be acceptable, and in some solutions, if the amount ofgelled polymer is too great, it can be removed by processes known in theart, such as filtration.

Embodiments of water soluble, crosslinked polymers provided herein arerandomly cross-linked among and along the hydrophilic polymer chains.Agents used for cross-linking are termed cross-linking agents orcross-linkers.

As used herein, “at least partially hydrophobic polymer matrices” arethose which comprise repeating units derived from hydrophobic componentssuch as hydrophobic monomers, macromers and prepolymers. Hydrophobiccomponents are those which are not soluble in water, and which whenhomopolymerized or polymerized with only other hydrophobic componentshave contact angles with respect to, for example, ophthalmic solutionssuch as wetting solutions of greater than about 90°. Examples of atleast partially hydrophobic polymer matrices include contact lensesformed from PMMA, silicones, silicone hydrogels (both coated anduncoated), stents, catheters and the like. Examples of hydrophobicmonomers, macromers and prepolymers are known and include monomers,macromers and prepolymers containing silicone groups, siloxane groups,unsubstituted alkyl groups, aryl groups and the like. Specific examplesinclude silicone containing components such as monomethacryloxypropylterminated mono-n-butyl terminated polydimethylsiloxanes (800-1000 MW)(mPDMS), monomethacryloxypropyl terminated mono-n-methyl terminatedpolydimethylsiloxanes, TRIS, methyl methacrylate, lauryl methacrylate,and the like.

As used herein, “stable” means that the compound does not undergo achange through a single autoclaving cycle of 121° C. for 30 minuteswhich would deleteriously affect the desired properties of either thewetting agent or the combination of the wetting agent and polymersubstrate. For example, ester bonds between the siloxane segment and thepolymer segment are in some embodiments undesirable. The autoclaving maybe conducted dry or in the presence of an ophthalmically compatiblesaline solution, such as, but not limited to borate or phosphatebuffered saline.

As used herein, “near-monodisperse” means a polydispersity index (PDI)of 1.5 or less and refers to an individual primary chain degree ofpolymerization and/or MW within a cluster of cross-linked amphiphilicprimary chains. In some embodiments, the polymers displaypolydispersities of less than about 1.3, and in others in the range ofabout 1.05 to about 1.3. It should be appreciated by those skilled inthe art that the individual near-monodisperse primary chains arestatistically cross-linked to one another during polymerization, and assuch, the resulting water soluble, cross-linked, polymer clusters willhave polydispersity values in excess of 1.5.

As used herein, “degree of polymerization” means the number of repeatingunits per polymer molecule or polymeric segment. For example, in one ormore embodiments, the copolymers of the present invention (prior tocrosslinking) can have a degree of polymerization in the range of about10 to about 10,000 (or about 50 to about 5000, or about 300 to about5000, or about 500 to about 2000, or about 100 to about 1000, or about100 to about 500, or about 100 to about 300).

As used herein, “cross-linker to primary chain molar ratio” (XL:ζ-PC)refers to the number of moles of cross-linker used during preparation ofthe copolymer in a ratio with the number of moles of primary chain usedin the preparation. The number of primary chains is determined by themolar amount of controlled radical polymerization (CRP) agent, orcontrol agent, present. Specific embodiments include a cross-linker toprimary chain molar ratio in the range of about 0.005 to about 10 (orabout 0.1 to about 5, or about 0.1 to about 1.5, or about 0.1 to about1.25). Exemplary CRP agents include, but are not limited to: reversibleaddition fragment transfer (RAFT) agents; atom transfer radicalpolymerization (ATRP) agents; telluride-mediated polymerization (TERP)agents; and/or nitroxide-mediated living radical polymerization (NMP)agents.

As used herein, “segment” or “block” refers to a section of polymerhaving repeating units with similar properties, such as composition orhydrophilicity.

As used herein, “silicone segment” refers to —[SiO]—. The Si atom ineach —[ SiO]-repeating unit may be alkyl or aryl substituted, arepreferably substituted with C₁₋₄ alkyl, and in one embodiment aresubstituted with methyl groups to form a dimethylsiloxane repeatingunit.

As used herein a “hydrophilic associative segment” is hydrophilic, butcan associate with the substrate via hydrogen, or ionic bonding. Forexample, for lenses which comprise a proton acceptor such as DMA, NVP orPVP, the hydrophilic associative segment comprises proton donatinggroups. In this example, suitable proton donating groups include4-acrylamidobutanoic acid (ACAII), N-hydroxyalkyl (meth)acrylamidemonomers such as N-(2-hydroxypropyl) methacrylamide, andN-(2,3-dihydroxypropyl)methacrylamide; or vinyl bezoic acid. It is abenefit of the present invention that the crosslinked nanogels do notcomprise separate associative segments, because the primary chains arethemselves capable of associating with the selected substrate.

As used herein “hydrophilic” polymers or monomers are those which yielda clear single phase when mixed with water at 25° C. at a concentrationof at least about 10 wt %.

As used herein, “complexing segments” or “complexing groups” includefunctional group pairs that exhibit strong non-covalent interactions,e.g. alkyl or aryl boronic acids that interact strongly with diolfunctional groups or biotin and avidin binding. In one embodiment, thecomplexing segments may comprise monomers such as (4-vinylphenyl)boronicacid, (3-acrylamidophenyl)boronic acid, or (4-acrylamidophenyl)boronicacid or N-(2-acrylamidoethyl)-5-((3 aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide.

As used herein, “stimuli responsive components” include those whichundergo a physical or chemical change in response to a change inenvironmental conditions. Conditions which can induce a change includepH, light, salt concentration, temperature, combinations thereof and thelike. Examples of monomers which can be used to prepare stimuliresponsive components include but are not limited toN-isopropylacrylamide, vinyl bezoic acid, or acrylamidobutanoic acid(ACAII), and the like.

As used herein “substrate” refers to an article, such as a sheet, film,tube or more complex form such as biomedical devices.

As used herein, a “biomedical device” is any article that is designed tobe used while either in or on mammalian tissues or fluid. Examples ofthese devices include but are not limited to catheters, implants,stents, sutures, bandages, and ophthalmic devices such as intraocularlenses and contact lenses and the like.

As used herein, the term “lens” refers to ophthalmic devices that residein or on the eye. These devices can provide optical correction, cosmeticenhancement, UV blocking and visible light or glare reduction,therapeutic effect, including wound healing, delivery of drugs ornutraceuticals, diagnostic evaluation or monitoring, or any combinationthereof. The term lens includes, but is not limited to, soft contactlenses, hard contact lenses, intraocular lenses, overlay lenses, ocularinserts, and optical inserts.

As used herein, a “silicone-containing polymer” is any polymercontaining silicone or siloxane repeating units. The silicone-containingpolymer may be a homopolymer, such as silicone elastomers, or acopolymer such as fluoro-silicones and silicone hydrogels. As usedherein, silicone hydrogel refers to a polymer comprising siliconecontaining repeating units and in some embodiments, a water content ofat least about 10%, and in some embodiments at least about 20%.

As used herein “RAFT polymerization” or “RAFT” refers to reversibleaddition fragmentation-chain transfer polymerization.

As used herein “reactive components” are the components in apolymerization reaction mixture which become part of the structure ofthe polymer upon polymerization. Thus, reactive components includemonomers and macromers which are covalently bound into the polymernetwork. Diluents and processing aids which do not become part of thestructure of the polymer are not reactive components.

As used herein “substituted” refers to alkyl groups which may containhalogens, esters, aryls, alkenes, alkynes, ketones, aldehydes, ethers,hydroxyls, amides, amines and combinations thereof.

As used herein “free radical source” refers to any suitable method ofgenerating free radicals such as the thermally induced homolyticscission of a suitable compound(s) (thermal initiators such asperoxides, peroxyesters, or azo compounds), the spontaneous generationfrom monomer (e.g., styrene), redox initiating systems, photochemicalinitiating systems or high energy radiation such as electron beam, X- orgamma-radiation. Chemical species known to act as “free radical sources”are commonly called initiators by those skilled in the art and will bereferred to as such for the purposes of this disclosure.

As used herein “proton donating segments” or “proton donating functionalgroups” are functional groups which have the ability to donate a protonto a proton accepting segment or group under lens forming, autoclavingor storage conditions. Proton donating functional groups includealcohols, acids, primary amides, and the like.

As used herein “proton accepting segments” or “proton acceptingfunctional groups” are functional groups which have the ability toaccept a proton under lens forming, autoclaving or storage conditions.Proton accepting groups include amines, amides, carbonyls and the like.

In one embodiment, the WSC polymer of the present invention is a stablepolymeric wetting agent, which is free of terminal substrate associatingsegments. Said polymers are comprised of material or polymer that has anaffinity for at least a portion of a medical device and provide thedesired improvements in substrate performance. The polymeric wettingagents may beneficially be associated with the substrate in a singlestep, without prior pretreatment.

Thus, the water soluble, crosslinked polymers are formed from componentswhich are hydrophilic and have an affinity for a given medical device.For example, the water soluble, crosslinked polymers may be formed fromcomponents that contain proton donating and proton accepting functionalgroups. In one such embodiment, the WSC polymers could contain multipleproton donating functional groups, such as alcohols, and thus have anaffinity for medical devices or other surfaces which proton areaccepting. Conversely, the water soluble, crosslinked polymers couldcontain multiple proton accepting functional groups, such as amides, andthus have an affinity for medical devices or other surfaces which areproton donating. Yet in other embodiments the WSC polymers could containmultiple ionic functional groups, such as carboxylates, sulfonates,ammonium salts, or phosphonium salts, and thus have an affinity formedical devices with an opposite charge to that of a given ionic thewater soluble, crosslinked polymers. In other embodiments the WSCpolymers contain functional groups capable of undergoing complexationwith other complementary functional groups on a medical device orsurface. For example, the water soluble, crosslinked polymers couldcontain multiple boronic acid functionalities and associate with amedical device or surface which contains multiple hydroxyl groups. In analternative embodiment, the hydroxyl groups may be contained within thewater soluble, crosslinked polymers and be associated with a surfacecontaining multiple boronic acid functional groups. In some embodiments,the water soluble, crosslinked polymer is stimuli responsive and iscomprised of functional groups that, when incorporated into polymericform, cause the resulting polymer to be water-soluble or water-insolubleunder different solution conditions. For example, the water soluble,crosslinked polymers might be comprised of a temperature-responsivepolymer, such as poly(N-isopropylacrylamide) (PNIPAM), which undergoes aphase-transition in water at 32° C. Therefore, at solution temperaturesbelow 32° C., said PNIPAM polymer is water-soluble and hydrophilic,while at higher solution temperatures (i.e. greater than 32° C.) it iswater-insoluble, hydrophobic, and able to associate with a medicaldevice or surface which contains at least one hydrophobe.

In one embodiment, the water soluble, crosslinked polymers formed by thecopolymerization of an ethylenically unsaturated monomer with apoly-functional ethylenically unsaturated monomer.

The hydrophilic primary chain, ζ, comprises statistically distributedrepeating units of G, D, and E with the following formulae:

The terms α, β, and γ, specify the relative molar amounts (in terms ofmole fraction) of G, D, and E that comprise the water soluble,crosslinked polymer. In some embodiments, α is equal to about 0.85 toabout 0.999, about 0.92 to about 0.999, about 0.95 to about 0.999, andabout 0.97 to about 0.999, while the sum of β and γ for each respectiverange of α would be equal to about 0.15 to about 0.001, about 0.08 toabout 0.001, about 0.05 to about 0.001, and about 0.025 to about 0.001.For the purposes of the disclosed invention, the mole fraction of D inthe water soluble, crosslinked polymer, (i.e. β) of a primary chain isintended to be maximized, compared to that of E (i.e. γ) thus maximizingthe number of cross-links between ζ and other ζ_(i)-primary chains, i.e.very few unreacted R′₁₅ moieties remain. All mole-fraction ranges of α,β, and γ are based on the relative amounts of monomer and cross-linkeremployed in the monomer feed of a given embodiment and assumes that thereactivity differences between vinyl-substituents on the monomer andcross-linker are minimal, i.e. near-statistical incorporation occurs. Inone embodiment, the nanogels of the present are substantially free fromunreacted R′₁₅ groups. When R′₁₅ comprises a double bond, this may beconfirmed via FTIR or other methods capable of detecting the presence ofdouble bonds. In one embodiment, R₁₅ and R′₁₅ are substantially free ofsiloxane repeating units and in another embodiment are substantiallyfree of silicone.

Structure I may contain a terminal thiocarbonylthio moiety, while inother embodiments, it may not.

U is selected from the group consisting of hydrogen, halogen, C₁-C₄alkyl which may be optionally substituted with hydroxyl, alkoxy, aryloxy(OR″), carboxy, acyloxy, aroyloxy (O₂CR″), alkoxy-carbonyl,aryloxy-carbonyl (CO₂R″) and combinations thereof. Preferably, U may beselected from H, or methyl.

V is independently selected from the group consisting of, R″, —CO₂H,—CO₂R″, —COR″, —CN, —CONH₂, —CONHR″, —CONR′₂, —O₂CR″, —OR″; plus cyclicand acyclic N-vinyl amides and combinations thereof.

R″ is independently selected from the group consisting of optionallysubstituted C₁-C₁₈ alkyl, C₂-C₁₈ alkenyl, aryl, heterocyclyl, alkarylwherein the substituents are independently selected from the group thatconsists of epoxy, hydroxyl, alkoxy, acyl, acyloxy, carboxy andcarboxylates, sulfonic acids and sulfonates, alkoxy- oraryloxy-carbonyl, isocyanato, cyano, silyl, halo, and dialkylamino;phosphoric acids, phosphates, phosphonic acids, phosphonates. In oneembodiment R″ is selected from the group consisting of methyl, —CH₂OH,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂—CO₂ ⁻, —CH₂CH₂—CO₂ ⁻, —CH₂CH₂CH₂—CO₂ ⁻,—CH₂CH₂CH₂CH₂—CO₂ ⁻, —CH₂CH₂CH₂CH₂CH₂—CO₂ ⁻, —CH₂— SO₃ ⁻, —CH₂CH₂—SO₃ ⁻,—CH₂CH₂CH₂—SO₃ ⁻, —CH₂CH₂CH₂CH₂—SO₃ ⁻, —CH₂CH₂CH₂CH₂CH₂— SO₃ ⁻,—(CH₃)₂—CH₂—CO₂ ⁻, —(CH₃)₂—CH₂—SO₃H, —CH₂CH₂CH₂—⁺N(CH₃)₂—CH₂CH₂—CO₂ ⁻,—CH₂CH₂—⁺N(CH₃)₂—CH₂CH₂—CO₂ ⁻, —CH₂CH₂CH₂—⁺N(CH₃)₂—CH₂CH₂CH₂—SO₃ ⁻,—CH₂CH₂—⁺N(CH₃)₂—CH₂CH₂CH₂—SO₃ ⁻, —CH₂CH₂CH₂—⁺N(CH₃)₂—CH₂CH₂CH₂—PO₃ ⁻²,—CH₂CH₂—⁺N(CH₃)₂—CH₂CH₂CH₂—PO₃ ⁻², —CH₂CH₂CH₂—⁺N(CH₃)₂—CH₂CH₂—PO₃⁻²—CH₂CH₂—⁺N(CH₃)₂—CH₂CH₂—PO₃ ⁻², and combinations thereof and the like.Examples of suitable V groups include pyrrolidonyl, piperidonyl,2-caprolactam, 3-methyl-2-caprolactam, 3-methyl-2-piperidonyl,4-methyl-2-piperidonyl, 4-methyl-2-caprolactam, 3-ethyl-2-pyrrolidonyl,4,5-dimethyl-2-pyrrolidonyl, imidazolyl, N—N-dimethylamido, amido,N,N-bis(2-hydroxyethyl)amido, -cyano, N-isopropyl amido, acetate, -,carboxypolyethylene glycol, N-(2-hydroxypropyl)amido,N-(2-hydroxyethyl)amido, carboxyethyl phosphorylcholine,3-(dimethyl(4-benzyl)ammonio)propane-1-sulfonate (DMVBAPS),3-((3-amidopropyl)dimethylammonio)propane-1-sulfonate (AMPDAPS),3-((3-(carboxy)propyl)dimethylammonio)propane-1-sulfonate (APDAPS),N-methylacetamide, -acetamide, N-methylpropionamide,N-methyl-2-methylpropionamide, 2-methylpropionamide, N,N′-dimethylurea,and the like, and mixtures thereof.

In one embodiment, V comprises —N—(CH₃)₂, pyrrolidonyl, —CON(CH₃)₂,N-(2-hydroxyethyl)amido or —N(CH₃)COCH₃.

R₁ can be any chemical moiety or polymer that is capable of initiatingfree-radical polymerization. In one embodiment, R¹ is capable ofundergoing reversible termination and fragmentation, e.g. as would beobserved under RAFT polymerization conditions, while also retaining theability to initiate polymerization. R₁ may be selected from divalentgroups consisting of optionally substituted alkylene; optionallysubstituted saturated, unsaturated or aromatic carbocyclic orheterocyclic rings; optionally substituted alkylthio; optionallysubstituted alkoxy; or optionally substituted dialkylamino. In oneembodiment, R₁ is selected from optionally substituted benzyl,optionally substituted phenyl, ethanoate, optionally substitutedpropionate, 4-cyanopentanoate, or isobutyroate functionalities. In oneembodiment, R₁ comprises a 4-cyanopentanoate, isobutanoic, or a benzylicgroup. In other embodiments, R₁ can comprise a cyano-methy or cumylgroup. In another embodiment, R₁ comprises said functional groups and ispolyvalent. Examples of stable copolymers are shown below in FormulaVIII with a range of suitable substituents.

R₁₈ comprises an agent which is capable of taking part and/or mediatinga controlled free radical polymerization (CRP). CRP techniques are wellknown to those of skill in the art and can include, but are not limitedto reversible addition fragmentation chain-transfer polymerization(RAFT), atom transfer radical polymerization (ATRP), nitroxide mediatedpolymerization (NMP), and Tellurium-mediated radical polymerization(TERP).

In one embodiment, the following copolymer structures may be formed viaRAFT and thus contain a thiocarbonylthio functional group on theterminus of each primary chain within a ζ-cluster:

It should be appreciated that the substitutions described above may becombined in any combination.

The WSC polymer generally has a degree of polymerization in the range ofabout 10 to about 10,000. In some embodiments, the degree ofpolymerization is at least about 100, or at least about 300, or even inothers at least about 500. In further embodiments, the water soluble,crosslinked polymer has a degree of polymerization within the followingranges: about 300 to about 10,000, about 300 to about 5,000, betweenabout 500 to about 10,000, about 500 to about 5,000 and about 500 toabout 2000 and about 700 to about 2000. Degree of polymerization may beobtained from MALDI-TOF, SEC-MALLS, NMR or a combination thereof.

Each ζ-primary chain is cross-linked or semi-cross-linked. That is,unlike previously disclosed art having only linear, branched, or combedstructures, the water soluble, crosslinked copolymer is randomlycross-linked via covalent, ionic, or hydrogen-bonds along the polymer.Cross-linking agents have two or more reactive or associativefunctionalities to react with and/or associate the copolymers of thepresent invention to one another. The residues of the cross-linkingagents are shown in Figure VII as R₁₅ and R₁₅′. Cross-linking agentscomprise free radical reactive functionality, such as vinyl, allyl,(meth)acrylate, (meth)acrylamide and the like. In one embodiment thecross-linking agents are hydrophilic, and in another do not comprisedimethylsiloxane groups, and in another embodiment are free of silicone.Exemplary covalent cross-linking agents include:N,N′-methylenebis(meth)acrylamide; N,N′-ethylenebis(meth)acrylamide;N,N′-propylenebis(meth)acrylamide; N,N′-butylenebis(meth)acrylamide;N,N′-pentamethylenebis(meth)acrylamide;N,N′-hexamethylenebis(meth)acrylamide; all otherN,N′-alkylenebis(meth)acrylamides; allpolyalkyleneglycoldi(meth)acrylates, including, but not limited toethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate,tetra-ethylene glycol di(meth)acrylate; and allpolyalkyleneglycoldi(meth)acrylamides, including, but not limited toN,N′-(oxybis(ethane-2,1-diyl))diacrylamideN,N′-(((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))diacrylamide,triallyl cyanurate (TAC), 1,3-divinylimidazolidin-2-one, and3,3″alkylenebis(1-vinylpyrrolidin-2-one), wherein the alkylene has 1-12carbons. The WSC polymers of the present invention are water soluble,and non-gelled.

Cross-linking agents which have functionality along the backbone whichcan be reversibly broken or cleaved can also be used. For example,N,N′-cystamine di(meth)acylamide may be used as a crosslinker. After thesemi-crosslinked block copolymer is associated with the substrate, thedisulfide bond in cystamine may be cleaved and reformed to create aninterpenetrating network which is more intimately entangled in thesubstrate matrix.

The molar ratio of RAFT agent to cross-linking agent in thecross-linking reaction mixture is greater than about 0.1, greater thanabout 0.2, greater than about 0.3, greater than about 0.5, greater thanabout 0.75, greater than about 1, greater than about 2, greater thanabout 5 and in some cases greater than about 10. In one embodiment thecross-linking agent is free of silicone and the RAFT agent tocross-linking agent in the cross-linking reaction mixture is greaterthan about 0.1. In embodiments where the cross-linking agent comprisessiloxane, the RAFT agent to cross-linking agent in the cross-linkingreaction mixture is greater than about 0.3. A molar ratio of the molaramount of cross-linking agent to theoretical primary chains (“XL:ζ-PC”)in the cross-linking reaction mixture can be between 0.01:1.0 and6.0:1.0, with the following non-limiting values of XL:ζ-PC beingpreferred: 0.1:1.0, 0.2:1.0, 0.25:1.0, 0.3:1.0, 0.4:1.0, 0.5:1.0,0.55:1.0, 0.6:1.0, 0.7:1.0, 0.75:1.0, 0.8:1.0, 0.9:1.0, 1.0:1.0,1.2:1.0, 1.25:1.0, 1.5:1.0, 3.0:1.0, 4.0:1.0, 5.0:1.0, 7.5:1.0 or even10:1.0. In some embodiments it may be desirable to select XL:ζ-PC valueswhich provide WSC polymers across a wide range of temperatures andsolution conditions, to allow for ready incorporation into a range ofarticles and solutions. For example, water soluble crosslinked polymerscomprising poly(N-(2-hydroxypropyl)methacrylamide) PHPMA, may desirablyhave an XL:ζ-PC of less than about 1.25:1 to prevent macroscopic gellingof the polymer. In other embodiments, the XL:ζ-PC for said example maybe less than 3:1. Yet in other embodiments, the XL:ζ-PC for said examplemay be less than 1.5:1. In other embodiments it may be desirable toselect XL:ζ-PC values which provide the desired decrease in lipid uptakeof the treated substrate, with increasing XL:ζ-PC values, decreasing thelipid uptake levels.

In addition to XL:ζ-PC, another factor that affects the point at whichmacroscopic gelation occurs is the total monomer concentration. In someembodiments of this invention, the total monomer concentration used caninclude, but is not limited to 1 to about 80 wt % and about 10 to about50 wt %, and still further about 20 to about 50 wt %.

Those of skill in the art will appreciate that the number of primarychains formed in a controlled radical polymerization (CRP) system isdictated by the concentration of a controlled radical polymerization(CRP) agent or control agent. In the case of a RAFT polymerization, thecontrol agent would be a thiocarbonylthio functional control agent. Inthe case of ATRP, the control agent would be a copper ligand complex.For the purposes of the invention disclosed herein, any CRP agent can beemployed. In other embodiments, a CRP agent may not be required, so longas nanogel formation is possible, without macroscopic gellation.

In one embodiment, the polymeric wetting agent has the general structureand primary chain designator, ζ, as shown in Formula IA.

Wherein R₁, R₁₅, R′₁₅, G, D, E, Z, ζ, ζ_(i), α, β, γ, m, and p aredefined below, and may be formed by contacting:

At least one hydrophilic monomer having the formula H₂C=UV

At least one RAFT agent of Formula II having a chain transfer constantgreater than 0.1;

(iii) free radicals produced from a free radical source (i.e. aninitiator); and

(iv) a cross-linking agent, H₂C=UR₁₅

Z is selected from the group consisting of hydrogen, chlorine, fluorine,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted alkylthio, optionallysubstituted alkoxy, optionally substituted alkoxycarbonyl, optionallysubstituted aryloxycarbonyl (—COOR″), carboxy (—COOH), optionallysubstituted acyloxy (—O₂CR″), optionally substituted carbamoyl(—CONR″₂), cyano (—CN), dialkyl- or diaryl-phosphonato [—P(═O)(OR″)₂],dialkyl- or diaryl-phosphinato [—P(═O)(OR″)₂], and a polymer chainformed by any mechanism;

-   -   p is 1 or an integer greater than 1, 1-5, 3-5 and in some        embodiments 1 or 2. When p≧2, then R₁ is selected from p-valent        moieties derived from any of silicon, sulfur, oxygen, nitrogen,        optionally substituted alkylene, optionally substituted aryl, a        polymer chain, or a combination thereof. Such an embodiment,        where p is p-valent, is disclosed in the following structural        analogues of Formulas I and II, namely Formulas VI and VII

In one embodiment where RAFT polymerization is employed, a RAFT agent,free-radical initiator, mono-vinyl monomer, and a di- or poly-vinylmonomer are combined at the desired molar ratios and dissolved in asolvent of choice. The resulting solution is polymerized to yield across-linked, but ungelled polymer with no distinct substrateassociating segments. Formula VI below details the structures for theRAFT-based CRP agents that might be used in such an embodiment.

Formula VIII Dithioates Trithiocarbonates Dithiocarbamates & Xanthates

It will be apparent to those skilled in the art that this results in theformation of ζ-clusters that contain primary chains without substrateassociative segments.

In one embodiment the hydrophilic primary chains, ζ, may be formed fromknown hydrophilic monomers, U. Hydrophilic monomers are those whichyield a clear single phase when mixed with water at 25° C. at aconcentration of 10 wt %. Examples of suitable families of hydrophilicmonomers include vinyl amides, vinylimides, vinyl lactams, hydrophilic(meth)acrylates, (meth)acrylamides, styrenics, vinyl ethers, vinylcarbonates, vinyl carbamates, vinyl ureas and mixtures thereof.

Examples of suitable hydrophilic monomers include N-vinyl pyrrolidone,N-vinyl-2-piperidone, N-vinyl-2-caprolactam,N-vinyl-3-methyl-2-caprolactam, N-vinyl-3-methyl-2-piperidone,N-vinyl-4-methyl-2-piperidone, N-vinyl-4-methyl-2-caprolactam,N-vinyl-3-ethyl-2-pyrrolidone, N-vinyl-4,5-dimethyl-2-pyrrolidone,vinylimidazole, N—N-dimethylacrylamide, acrylamide,N,N-bis(2-hydroxyethyl)acrylamide, acrylonitrile, N-isopropylacrylamide, vinyl acetate, (meth)acrylic acid, polyethylene glycol(meth)acrylates, 2-ethyl oxazoline, N-(2-hydroxypropyl)(meth)acrylamide, N-(2-hydroxyethyl) (meth)acrylamide,2-methacryloyloxyethyl phosphorylcholine,3-(dimethyl(4-vinylbenzyl)ammonio)propane-1-sulfonate (DMVBAPS),3-((3-acrylamidopropyl)dimethylammonio)propane-1-sulfonate (AMPDAPS),3-((3-methacrylamidopropyl)dimethylammonio)propane-1-sulfonate(MAMPDAPS), 3-((3-(acryloyloxy)propyl)dimethylammonio)propane-1-sulfonate (APDAPS),methacryloyloxy)propyl)dimethylammonio)propane-1-sulfonate (MAPDAPS), N,N-dimethylaminopropyl(meth)acrylamide, N-vinyl-N-methylacetamide,N-vinylacetamide, N-vinyl-N-methylpropionamide,N-vinyl-N-methyl-2-methylpropionamide, N-vinyl-2-methylpropionamide,N-vinyl-N,N′-dimethylurea, and the like, and mixtures thereof. In oneembodiment the hydrophilic monomer comprises N-vinyl pyrrolidone,N-vinyl-N-methylacetamide, 2-methacryloyloxyethyl phosphorylcholine,(meth)acrylic acid, N,N-dimethylacrylamide N-hydroxypropylmethacrylamide, mono-glycerol methacrylate, 2-hydroxyethyl acrylamide,bishydroxyethyl acrylamide, and 2,3-dihydroxypropyl (meth)acrylamide andthe like and mixtures thereof. In some embodiments the hydrophilicsegment may also comprise charged monomers including but not limited tomethacrylic acid, acrylic acid, 3-acrylamidopropionic acid (ACA1),4-acrylamidobutanoic acid, 5-acrylamidopentanoic acid (ACA2),3-acrylamido-3-methylbutanoic acid (AMBA), N-vinyloxycarbonyl-α-alanine,N-vinyloxycarbonyl-β-alanine (VINAL),2-vinyl-4,4-dimethyl-2-oxazolin-5-one (VDMO), reactive sulfonate salts,including, sodium-2-(acrylamido)-2-methylpropane sulphonate (AMPS),3-sulphopropyl (meth)acrylate potassium salt, 3-sulphopropyl(meth)acrylate sodium salt, bis 3-sulphopropyl itaconate di sodium, bis3-sulphopropyl itaconate di potassium, vinyl sulphonate sodium salt,vinyl sulphonate salt, styrene sulfonate, sulfoethyl methacrylate,N,N-dimethylaminopropyl acrylamide (DMAPA),3-acrylamido-N,N,N-trimethylpropan-1-ammonium chloride (i.e. methylquaternized DMAPA), combinations thereof and the like. In embodimentswhere the hydrophilic segment comprises at least one charged hydrophilicmonomer it may be desirable to include non-charged hydrophilic monomersas comonomers in the hydrophilic segment. In another embodiment thecharged hydrophilic monomer is randomly distributed throughout the [Q]segment.

The WSC polymers may be formed via a number of polymerization processes.In one embodiment the WSC polymers are formed using RAFT polymerization.In other embodiments the block copolymers are formed using ATRP. Whilein another embodiment, the block copolymers are formed using TERP. Stillyet, in some embodiments the block copolymers are formed using any knowncontrolled radical polymerization mechanism. In another embodiment thewater soluble, crosslinked polymers are formed by conventional freeradical polymerization. In one embodiment, the WSC polymers may beformed by conventional free radical polymerization or by othernon-controlled mechanisms of polymerization. It is obvious to those ofskill in the art, however, that the synthetic utility of such routes isfairly limited (compared to controlled polymerization), i.e.non-controlled polymerizations must be conducted under dilute conditions(with respect to monomer and cross-linker) and typically do not reachhigh conversion without the formation of a macroscopic gel. In addition,much lower XL:ζ-PC ratios must be targeted to prevent macroscopicgelation. The water soluble, crosslinked polymer does not containseparate terminal substrate associative blocks. Instead, the watersoluble, crosslinked polymer contains either a single block, whichdisplays both affinity for the substrate and the desired performanceenhancing properties or contains multiple blocks all of which displayboth affinity for the substrate and the desired performance enhancingproperties. The water soluble, cross-linked polymers may also compriserandom copolymers. Exemplary embodiments of such water soluble,crosslinked polymer include water soluble crosslinked polymers andcopolymers of N-vinyl pyrrolidone, N,N-dimethyl acrylamide,N-hydroxypropyl methacrylamide, mono-glycerol methacrylate,2-hydroxyethyl acrylamide, and bishydroxyethylacrylamide,2,3-dihydroxypropyl (meth)acrylamide. Alternatively twodifferent polymers or copolymers may be crosslinked together to form thecopolymers of the present application. In one embodiment of the presentapplication random copolymers are preferred. In another embodiment thewater soluble, cross-linked polymers are contacted with ophthalmicdevices, such as contact lenses. In this embodiment, it may be desirablefor the contact lenses to have low uptake of components, such aspreservatives, such as PQ-1, from cleaning and care solutions. In theseembodiments the polymers are free from repeating units derived fromacrylic acid or substituted acrylic acids, including methacrylic acid.

Embodiments can be used to treat conventional or silicone hydrogelmaterials, provided the affinity of the water soluble, crosslinkedcopolymer is tailored to the surface of the lens or device beingtreated. The water soluble, crosslinked copolymer with appropriatefunctionality and architecture can closely mimic the behavior of boundmucins found on corneal epithelial surfaces and could be very useful inmodifying the surface of a contact lens medical device to improve itslubricity, deposit uptake, and possibly comfort. Without intending to bebound by theory, it is speculated that the cross-linked nature of thewater soluble, crosslinked copolymer could closely mimic themucin-N-mucin interactions that occur through disulfide cross-linking,H-bonding, and molecular entanglement.

Polymerization Conditions

The number average molecular weight of each ζ-primary chain, M_(n)_(ζ-PC) , in a given polymerization produced from contacting a RAFTagent (when required), with at least one hydrophilic monomer, freeradical initiator, and cross-linking agent can be targeted using thefollowing equation:

where

$\begin{matrix}{M_{n_{\zeta - {PC}}} = {M_{n_{M}} + M_{n_{XL}} + {M\; W_{CTA}}}} & \left( {{equation}\mspace{14mu} 1} \right) \\{M_{n_{M}} = {{\frac{\lbrack M\rbrack}{\left( \lbrack{CTA}\rbrack \right)} \cdot X \cdot M}\; W_{monomer}\mspace{14mu}{and}}} & \left( {{Equation}\mspace{14mu} 2} \right) \\{M_{n_{XL}} = {{\frac{\lbrack{XL}\rbrack}{\left( \lbrack{CTA}\rbrack \right)} \cdot \frac{X}{\psi} \cdot M}\; W_{XL}}} & \left( {{Equation}\mspace{14mu} 3} \right)\end{matrix}$

M_(n) _(M) , M_(n) _(XL) , and MW_(CTA) represent the individualcontributions of molecular weight for the monomer, cross-linker, andRAFT agent that (when summed) are equal to the number average molecularweight of a ζ-primary chain, i.e. M_(n) _(ζ-PC) . ψ is the number ofreactive functional groups on the crosslinker, [M] is the reactivemonomer concentration, [XL] is the cross-linker concentration, X is theextent of conversion in fractional form, [CTA] is the concentration ofRAFT agent, and MW_(monomer), MW_(XL), and MW_(CTA) are the molecularweights of reactive monomer, cross-linker, RAFT agent, respectively.

The predicted degree of polymerization (DP) for the hydrophilic polymersegment, DP_(ζ-PC), can be calculated from Equations 1, 2, and 3. If Xis unity (i.e. the polymerization reaches 100% conversion) and MW_(CTA)is neglected because M_(n) _(ζ-PC) >>MW_(CTA), Equation 1 reduces toEquation 4:M _(n) _(ζ-PC) =M _(n) _(M) +M _(n) _(XL)   (Equation 4)M _(n) _(Q-Segment) =M _(n) _(M) +M _(n) _(XL)Solving the equation in terms of DP_(ζ-chain) by dividing M_(n) _(M) andM_(n) _(XL) by their respective monomeric masses, MW_(M) and MW_(XL)gives:

$\begin{matrix}\begin{matrix}{{DP}_{n_{Q - {segment}}} = {\frac{M_{n_{M}}}{M\; W_{M}} + \frac{M_{n_{XL}}}{\frac{M\; W_{XL}}{\psi}}}} \\{= {{DP}_{n_{M}} + \frac{{DP}_{n_{XL}}}{\psi}}}\end{matrix} & \left( {{Equation}\mspace{14mu} 5} \right) \\{{DP}_{n_{\zeta - {PC}}} = {\frac{\lbrack M\rbrack}{\left( \lbrack{CTA}\rbrack \right)} + {\frac{\lbrack{XL}\rbrack}{\left( \lbrack{CTA}\rbrack \right)} \cdot \frac{1}{\psi}}}} & \left( {{Equation}\mspace{14mu} 6} \right)\end{matrix}$

It should be apparent to those of skill in the art that while theseequations do predict the number average molecular weight of a ζ-primarychain, M_(n) _(ζ-PC) , they do not predict the total DP or overallaverage molecular weight of a ζ-cluster, which are formed due to theparticipation of the cross-linker in the RAFT polymerization and thefact that ζ-primary chains become randomly cross-linked to each otherand to other growing ζ-clusters. The MW of a given ζ-cluster is muchhigher than that of an individual ζ-primary chain found within thatζ-cluster and may or may not be an exact multiple of the average M_(n)_(ζ-PC) for a given polymerization.

One target DP_(n) _(PC) is in the range of about 10 to 10,000, with 50to 1500 being preferred, 50 to 1000 being more preferred, and 50-500being most preferred.

Polymerization conditions for the polymerization of the hydrophilicmonomer in the presence of the appropriate RAFT agent and cross-linkingagent to form the water soluble, crosslinked polymer are selected basedupon the initiator system used and to provide the desired balancebetween chain growth and termination. Other polymerization components,such as solvents, initiator and additives may also be selected such thatthey have a low transfer constant toward the propagating radical and arefully miscible with all other polymerization components.

The cross-linker may be added to the polymerization solution at thebeginning of the reaction or withheld until a later point in thereaction to manipulate the architecture of the resulting nanogelmaterial in a way that gives a desired structure or property.Alternatively, the reactive groups on the cross-linker may be selectedsuch that incorporation into the propagating polymer backbones is lessrandom and thus forms polymeric nanogels that have a less evenlydistributed cross-link density. If a polymeric nanogel with more“blocky” incorporation of the cross-linker is desired, a crosslinkerwith a different reactivity to that of the propagating mono-vinylmonomer may be used. For example, a dimethacrylated cross-linker may beemployed in the formation of a nanogel with an acrylamido, mono-vinylmonomer. For some embodiments that exploit CRP, this would result in a“tapered” incorporation of the cross-linker into the primary polymerchain backbone, i.e. one end of each primary polymer chain would bericher in divinyl monomer than the other. Alternatively, for embodimentswhere a random distribution of the cross-linker throughout the primarypolymer chain is desired, the cross-linker may be selected so that bothof its reactive sites have similar reactivities (or identical functionalgroups) to that of the propagating mono-vinyl monomer. In someembodiments, cross-linkers containing functional groups with differentreactivities, e.g. 2-(acryloyloxy)ethyl methacrylate orN-(2-acrylamidoethyl)methacrylamide, may be employed. Those skilled inthe art would expect such structures to also incorporate across eachprimary polymer chain in a less-random fashion to that of an analogoussystem which contains matched reactivities for all reactive functionalgroups.

In embodiments where the block WSC polymer is made via RAFT, theinitiating system is chosen such that under the reaction conditionsthere is no substantial adverse interaction(s) of the initiator or theinitiating radicals with the transfer agent. The initiator should alsohave the requisite solubility in the reaction medium or monomer mixture.The initiator is selected based upon the hydrophilic monomer selected.For example, where free radical reactive hydrophilic monomers are used,the initiator may be any initiator capable of providing a radicalsource, such as photoinitiators, thermal initiators, redox initiatorsand gamma initiators. Suitable photoinitiators include the UV andvisible photoinitiators described below. Thermal initiators are chosento have an appropriate half life at the temperature of polymerization.These initiators can include one or more of the following compounds:2,2′-azobis(isobutyronitrile), 2,2′-azobis(2-cyano-2-butane),2,2′-Azobis[2-(2-imidazol-N-2-yl)propane]dihydrochloridedimethyl(VA-044), 2,2′-azobisdimethylisobutyrate 4,4′-azobis(4-cyanopentanoicacid), 1,1′-azobis(cyclohexanecarbonitrile,2-(t-butylazo)-2-cyanopropane,2,2′-azobis[2-methyl-N-(1,1)-bis(hydroxymethyl)-2-hydroxyethyl]propionamide,2,2′-azobis[2-methyl-N-hydroxyethyl)]-propionamide,2,2′-azobis(N,N′-dimethyleneisobutyramidine)dihydrochloride,2,2′-azobis(2-amidinopropane)dihydrochloride,2,2′-azobis(N,N′-dimethyleneisobutyramine),2,2′-azobis(2-methyl-N-[1,1-bis(hydroxymethyl)-2-hydroxyethyl]propionamide),2,2′-azobis(2-methyl-N-[1,1-bis(hydroxymethyl)ethyl]propionamide),2,2′-azobis[2-methyl-N-(2-hydroxyethyl) propionamide],2,2′-azobis(isobutyramide)dihydrate,2,2′-azobis(2,2,4-trimethylpentane), 2,2′-azobis(2-methylpropane),t-butyl peroxyacetate, t-butyl peroxybenzoate, t-butyl peroxyoctoate,t-butyl peroxyneodecanoate, t-butylperoxy isobutyraate, t-amylperoxypivalate, t-butyl peroxypivalate, di-isopropyl peroxydicarbonate,dicyclohexyl peroxydicarbonate, dicumyl peroxide, dibenzoyl peroxide,dilauroyl peroxide, potassium peroxydisulfate, ammonium peroxydisulfate,di-t-butyl hyponitrite, dicumyl hyponitrite. In one embodiment, thethermal initiator is selected from initiators that generate freeradicals at moderately elevated temperatures, such as lauryl peroxide,benzoyl peroxide, isopropyl percarbonate, azobisisobutyronitrilecombinations thereof, and the like.

Examples of redox initiators include combinations of the followingoxidants and reductants:

oxidants: potassium peroxydisulfate, hydrogen peroxide, t-butylhydroperoxide.

reductants: iron (II), titanium (III), potassium thiosulfite, potassiumbisulfate.

In one embodiment, the initiator is selected from photoinitiators whichhave the requisite solubility in the reaction medium or monomer mixtureand have an appropriate quantum yield for radical production under theconditions of the polymerization. Examples include benzoin derivatives,benzophenone, acyl phosphine oxides, and photo-redox systems. In anotherembodiment the initiator is selected from visible initiators selectedfrom 1-hydroxycyclohexyl phenyl ketone,2-hydroxy-2-methyl-1-phenyl-propan-1-one,bis(2,6-dimethoxybenzoyl)-2,4-4-trimethylpentyl phosphine oxide(DMBAPO), bis(2,4,6-trimethylbenzoyl)-phenyl phosphineoxide (Irgacure819), 2,4,6-trimethylbenzyldiphenyl phosphine oxide and2,4,6-trimethylbenzoyl diphenylphosphine oxide, benzoin methyl ester anda combination of camphorquinone and ethyl 4-(N,N-dimethylamino)benzoate,combinations thereof and the like. In another embodiment the initiatorcomprises at least one phosphine oxide containing photoinitiator, and inanother embodiment, bis(2,4,6-trimethylbenzoyl)-phenyl phosphineoxide.When a photoinitiator is used, the reaction mixture is irradiated usingradiation in the activating wavelength for the selected photoinitiator.

The polymerization may be conducted in solution, suspension or emulsion,under batch, continuous or feed mode. In one embodiment the process isconducted by adding polymerization agent to the reaction mixturecontaining the chain transfer agent. Other conditions may be used andare known in the art.

The copolymers provided herein may be purified via known means such assolvent precipitation and/or subsequent solvent extractions or bydialysis or related purification techniques such as, but not limited totangential flow filtration (TFF).

In some embodiments where RAFT polymerization is used and where the RAFTagent is not removed prior to use, a RAFT polymerization agent isretained at the terminal end of the WSC polymer.

The RAFT polymerization agents are not thermally or hydrolyticallystable, and thus it is a benefit of embodiments of the present inventionthat the RAFT polymerization agents are at the terminal end as they maybe readily cleaved or replaced prior to incorporation into the polymersubstrates. Alternatively, the RAFT polymerization agent may be left onthe WSC polymer and either cleaved during incorporation into the polymersubstrate or during use (if the RAFT and/or its degradants arenon-toxic, non-irritating). In one embodiment the RAFT polymerizationagent is removed prior to incorporating the WSC polymers into thesubstrates, or the solutions to be contacted with the substrates.Suitable processes for removing the end groups include, but are notlimited to reaction with amines, such as disclosed in U.S. Pat. No.7,109,276, U.S. Pat. No. 6,794,486, U.S. Pat. No. 7,807,755,US2007232783, US2010137548, U.S. Pat. No. 5,385,996, and U.S. Pat. No.5,874,511. Other end-group removal techniques, such as thermolysis orradical reduction, may be employed in some embodiments as well.

In one embodiment, the WSC polymers have the structure represented inFormula I, above.

In another embodiment, the WSC polymers may be formed using conventionalfree radical reactions. In this embodiment the block copolymers may beformed by the free radical reaction of at least one hydrophilic monomerand an azo-type macro initiator.

Hydrophobic or Partially Hydrophobic Substrates

The WSC polymers disclosed herein may be non-covalently associated witha variety of hydrophobic, partially hydrophobic, hydrophilic, oramphiphilic substrates, such as polymeric articles formed frompolysiloxanes, silicone hydrogels, conventional hydrogels, polymethylmethacrylate, polyethylene, polypropylene, polycarbonate, polyethyleneterapthalate, polytetrafluoroethylene, glass, metal and mixtures andcopolymers thereof and the like. The association occurs, provided thereis sufficient affinity between the functional groups contained withinthe water soluble, crosslinked copolymer and those found on or within agiven substrate. Examples of substrates which may be treated toassociate the copolymers of the present invention therewith includepolymers and metals used for implantable devices, sutures, graftsubstrates, punctal plugs, catheters, stents, wound dressings, surgicalinstruments, ophthalmic devices and the like.

Additional examples of at least partially hydrophobic polymer matricesinclude highly crosslinked ultra high molecular weight polyethylene(UHMWPE), which is used for implantable devices, such as jointreplacements, are made typically has a molecular weight of at leastabout 400,000, and in some embodiments from about 1,000,000 to about10,000,000 as defined by a melt index (ASTM D-1238) of essentially 0 andreduced specific gravity of greater than 8 and in some embodimentsbetween about 25 and 30.

Absorbable polymers suitable for use as yarns in making sutures andwound dressings include but are not limited to aliphatic polyesterswhich include but are not limited to homopolymers and copolymers oflactide (which includes lactic acid d-,l- and meso lactide), glycolide(including glycolic acid), ε-caprolactone, p-dioxanone(1,4-dioxan-2-one), trimethylene carbonate (1,3-dioxan-2-one), alkylderivatives of trimethylene carbonate, δ-vaterolactone, β-butyrolactone,γ-butyrolactone, ε-decalactone, hydroxybutyrate, hydroxyvalerate,1,4-dioxepan-2-one (including its dimer1,5,8,12-tetraoxacyclotetradecane-7,14-dione), 1,5-dioxepan-2-one,6,6-dimethyl-1,4-dioxan-2-one and polymer blends thereof.

Non-absorbable polymer materials such as but are not limited to,polyamides (polyhexamethylene adipamide (nylon 66), polyhexamethylenesebacamide (nylon 610), polycapramide (nylon 6), polydodecanamide (nylon12) and polyhexamethylene isophthalamide (nylon 61) copolymers andblends thereof), polyesters (e.g. polyethylene terephthalate, polybutylterephthalate, copolymers and blends thereof), fluoropolymers (e.g.polytetrafluoroethylene and polyvinylidene fluoride) polyolefins (e.g.polypropylene including isotactic and syndiotactic polypropylene andblends thereof, as well as, blends composed predominately of isotacticor syndiotactic polypropylene blended with heterotactic polypropylene(such as are described in U.S. Pat. No. 4,557,264 issued Dec. 10, 1985assigned to Ethicon, Inc. hereby incorporated by reference) andpolyethylene (such as is described in U.S. Pat. No. 4,557,264 issuedDec. 10, 1985 assigned to Ethicon, Inc. and combinations thereof.

The body of the punctal plugs may be made of any suitable biocompatiblepolymer including, without limitation, silicone, silicone blends,silicone co-polymers including, for example, hydrophilic monomers ofpHEMA (polyhydroxyethlymethacrylate), polyethylene glycol,polyvinylpyrrolidone, glycerol, and the like. Other suitablebiocompatible materials include, for example fluorinated polymers, suchas, for example, polytetrafluoroethylene (“PTFE”), polyvinylidenefluoride (“PVDF”), and teflon; polypropylene; polyethylene; nylon; andethylene vinyl alcohol (“EVA”).

Polymeric parts of ultrasonic surgical instruments may be made frompolyimides, fluora ethylene propene (FEP Teflon), PTFE Teflon, siliconerubber, EPDM rubber, any of which may be filled with materials such asTeflon or graphite or unfilled. Examples are disclosed in US20050192610and U.S. Pat. No. 6,458,142. For these embodiments, the WSC polymer maybe mixed with a solvent that swells the at least partially hydrophobicpolymer matrix and then contacted with the polymer matrix.

In one embodiment, the WSC polymers are associated with preformedarticles including silicone ophthalmic devices such as lenses orpunctual plugs, silicone hydrogel articles, such as silicone hydrogellenses. Hydrophilic groups in the water soluble, crosslinked copolymerassociate with complementary groups on or in the preformed articles. Inthis embodiment, the copolymer is dissolved in a solvent which alsoswells the substrate. The polymer substrate is contacted with a solutioncomprising the copolymer. When the substrate is a silicone hydrogelarticle, such as a contact lens, suitable solvents include packingsolution, storing solution and cleaning solutions. Using this embodimentas an example, the silicone hydrogel lens is placed in a packingsolution comprising the copolymer. The copolymer is present in thesolution in amounts between about 0.001 and about 10%, in someembodiments between about 0.005 and about 2% and in other embodimentsbetween about 0.01 and about 0.5 weight %, based upon all components inthe solution.

The packing solutions may be any water-based solution that is used forthe storage of contact lenses. Typical solutions include, withoutlimitation, saline solutions, other buffered solutions, and deionizedwater. The preferred aqueous solution is saline solution containingsalts including, without limitation, sodium chloride, sodium borate,sodium phosphate, sodium hydrogenphosphate, sodium dihydrogenphosphate,or the corresponding potassium salts of the same. These ingredients aregenerally combined to form buffered solutions that include an acid andits conjugate base, so that addition of acids and bases cause only arelatively small change in pH. The buffered solutions may also be usedto clean or treat contact lenses. When the solutions of the presentinvention are used for cleaning, treatment or care of contact lensesthey may include additional components useful for such solutions,including viscosity adjusting agents, antimicrobial agents, wettingagents, anti-stick agents, preservatives, polyelectrolytes, stabilizers,chelants, antioxidants, combinations thereof and the like. Examples ofadditional components include 2-(N-morpholino)ethanesulfonic acid (MES),sodium hydroxide, 2,2-bis(hydroxymethyl)-2,2′,2″-nitrilotriethanol,n-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid, citric acid,sodium citrate, sodium carbonate, sodium bicarbonate, acetic acid,sodium acetate, ethylenediamine tetraacetic acid and the like andcombinations thereof. Preferably, the solution is a borate buffered orphosphate buffered saline solution.

The WSC polymer may also be associated with the lens using organicsolvents (with or without water as a co-solvent). In one embodiment, anorganic solvent is used to both swell the medical device, e.g. a contactlens medical device, and dissolve the WSC polymer so that it may beimbibed. Suitable solvents may be selected to swell the medical device,to dissolve the block copolymer or both. In another embodiment thesolvents may also be biocompatible so as to simplify manufacturing. Thesubstrate is contacted with the WSC polymer under conditions sufficientto incorporate a lubricious and wetting effective amount of the WSCpolymer. As used herein, a lubricious effective amount, is an amountnecessary to impart a level of lubricity which may be felt manually(such as by rubbing the device between one's fingers) or when the deviceis used. Additionally, as used herein, a wetting effective amount is anamount necessary to impart a level of increased wettability to the lens,as determined via known contact angle measurement techniques (i.e.sessile drop, captive bubble, or dynamic contact angle measurements). Ithas been found that in one embodiment, where the device is a softcontact lens, amounts of WSC polymer as little as 50 ppm provideimproved lens “feel” and lowered surface contact angles, as measured bysessile drop. Amounts of WSC polymer greater than about 50 ppm, and morepreferably amounts greater than about 100 ppm in the processingpackaging, storing or cleaning solution, add a more pronouncedimprovement in feel. Thus, in this embodiment, the WSC polymer mayincluded in a solution in concentrations up to about 50,000 ppm, in someembodiments between about 10 and 5000 ppm, and in some embodimentsbetween about 10 and about 2000 ppm. In one embodiment the solutioncomprising the block copolymer is free from visible haze (clear). Thepackaged lens may be heat treated to increase the amount of WSC polymerwhich permeates and becomes entangled in the lens. Suitable heattreatments, include, but are not limited to conventional heatsterilization cycles, which include temperatures of about 120° C. fortimes of about 20 minutes and may be conducted in an autoclave. If heatsterilization is not used, the packaged lens may be separately heattreated. Suitable temperatures for separate heat treatment include atleast about 40° C., and preferably between about 50° C. and the boilingpoint of the solution. Suitable heat treatment times include at leastabout 10 minutes, and in some embodiments from about 10 to about 30minutes. It will be appreciated that higher temperatures will requireless treatment time.

It is a benefit of the present invention that the step of associatingthe WSC polymer with the desired substrate may be conducted in a singlestep without pretreatment, covalent reaction or tie layers. However, insome embodiments it may be desirable to contact the substrate/WSCpolymer construct with an additional polymer or nanogel which containproton receiving groups to form a layered coating. The additionalpolymer may be linear, branched or crosslinked, and may have associatinggroups located at an end of the polymer, or throughout the polymer. Eachadditional polymer comprises groups which are capable of associating orreacting with groups contained in the polymer of the preceding layer.Several alternating layers of WSC and second polymer may be applied.Examples of polymers comprising proton receiving groups include but arenot limited to poly-N-vinyl pyrrolidone, poly-N-vinyl-2-piperidone,poly-N-vinyl-2-caprolactam, poly-N-vinyl-3-methyl-2-caprolactam,poly-N-vinyl-3-methyl-2-piperidone, poly-N-vinyl-4-methyl-2-piperidone,poly-N-vinyl-4-methyl-2-caprolactam, poly-N-vinyl-3-ethyl-2-pyrrolidone,and poly-N-vinyl-4,5-dimethyl-2-pyrrolidone, polyvinylimidazole,poly-N—N-dimethylacrylamide, polyvinyl alcohol, polyethylene-oxide,poly-2-ethyl-oxazoline, heparin polysaccharides, polysaccharides,mixtures and copolymers (including block or random, branched,multichain, comb-shaped or star shaped) thereof. Polymers and copolymersof Poly-N-vinylpyrrolidone (PVP) and poly-N—N-dimethylacrylamide may beused.

The second solution may be any of the solutions described above forcontacting the substrates with the WSC polymer. The at least one secondpolymer may be present in the solution in concentrations up to about50,000 ppm, between about 10 and 5000 ppm, or between about 10 and about2000 ppm. Because both polymers are non-ionic, the additional treatingsteps may be done at pH between about 6 and 8 and in some embodiments atabout 7.

Many silicone hydrogel materials are known and may be used, includingbut not limited to senofilcon, galyfilcon, lotrafilcon A and lotrafilconB, delefilcon, balafilcon, comfilcon, osmofilcon, enfilcon, filcon II,filcon IV and the like. Almost any silicone hydrogel polymer can betreated using the WSC polymers provided herein, including but notlimited to those disclosed in U.S. Pat. No. 6,637,929; WO03/022321;WO03/022322; U.S. Pat. No. 5,260,000; U.S. Pat. No. 5,034,461; U.S. Pat.No. 6,867,245; WO2008/061992; U.S. Pat. No. 5,760,100; U.S. Pat. No.7,553,880; US20100048847; and US2006/0063852.

Similar processes may be used for substrates made from polymers otherthan silicone hydrogels. The primary change will be in the selection ofthe solvent, which should solubilize the WSC polymer and either swellthe substrate or shrink or compact the WSC polymer. Mixtures of solventsmaybe used, and additional components, such as surfactants may beincluded if desired. For example where the article is a silicone articlesuch as a silicone contact lens or a silicone punctal plug, the WSCpolymer may be dissolved in a solvent such as aliphatic alcohols, waterand mixtures thereof. Specific examples include isopropanol, n-propanoland the like, at the concentrations described above.

In another embodiment, the WSC polymer may be included in the reactionmixture from which the polymeric article is made. In such an embodiment,effective amounts of WSC polymer might include quantities from about0.1% to 50% of the total weight of all lens components, with quantitiesfrom about 1% to 20% being more preferred, and quantities from about 2%to 15% being most preferred. For example, where the article is asilicone hydrogel contact lens, the WSC polymer may be included, inamounts up to about 20 weight % in the contact lens reaction mixturewith one or more silicone-containing components and one or morehydrophilic components. The silicone-containing components andhydrophilic components used to make the polymers disclosed herein can beany of the known components used in the prior art to make siliconehydrogels. These terms, specifically silicone-containing component andhydrophilic component, are not mutually exclusive, in that, thesilicone-containing component can be somewhat hydrophilic and thehydrophilic component can comprise some silicone, because thesilicone-containing component can have hydrophilic groups and thehydrophilic components can have silicone groups.

One advantage of the copolymers disclosed herein is in embodiments wherethe WSC polymer is formed by RAFT, the molecular weight (MW) andmolecular weight distribution (MWD) may be readily controlled dependingon the requirements of manufacture for the chosen article. For example,in one embodiment where the WSC polymer is incorporated into a lowviscosity reactive monomer mix, such as those used to form cast moldedcontact lenses, the MW of the block copolymer may be kept below about100,000 g/mol. In one embodiment where controlled polymerization isused, the polydispersity of the ζ-primary chains is less than about 1.3.The ζ-cluster will have polydispersity values greater than 1.3. Havinglower MW WSC polymer allows addition of a higher concentration of theWSC polymers according to embodiments of the present invention comparedto commercially available polymers, such as PVP. Conventional polymers,such as PVP, have higher polydispersities, which can result in extremelyviscous monomer mixes that tend to have processing issues due tostringiness.

The use of RAFT to prepare the WSC polymers of the present inventionallows for the formation of nano-sized gels without the formation ofmacroscopically gelled polymer. In addition to this, such nanogelsexhibit significantly lowered viscosities, when compared to the samelinear polymers with equivalent molecular weights. As mentioned above,high molecular weight polymers with lower viscosities can be desirablefor a variety of process applications, including minimizing theviscosity and stringiness of a given reactive monomer mix formulation.

A silicone-containing component is one that contains at least one[—Si—O—] group, in a monomer, macromer or prepolymer. In one embodiment,the Si and attached O are present in the silicone-containing componentin an amount greater than 20 weight percent, and in another embodimentgreater than 30 weight percent of the total molecular weight of thesilicone-containing component. Useful silicone-containing componentscomprise polymerizable functional groups such as (meth)acrylate,(meth)acrylamide, N-vinyl lactam, N-vinylamide, and styryl functionalgroups. Examples of silicone-containing components which are useful maybe found in U.S. Pat. Nos. 3,808,178; 4,120,570; 4,136,250; 4,153,641;4,740,533; 5,034,461; 5,760,100; 4,139,513; 5,998,498; US2006/0063852;and U.S. Pat. No. 5,070,215; and EP080539. All of the patents citedherein are hereby incorporated in their entireties by reference. Thesereferences disclose many examples of olefinic silicone-containingcomponents.

Suitable silicone-containing components include compounds of thefollowing formula:

where R² is independently selected from monovalent reactive groups,monovalent alkyl groups, or monovalent aryl groups, any of the foregoingwhich may further comprise functionality selected from hydroxy, amino,oxa, carboxy, alkyl carboxy, alkoxy, amido, carbamate, carbonate,halogen or combinations thereof; and monovalent siloxane chainscomprising 1-100 Si—O repeat units which may further comprisefunctionality selected from alkyl, hydroxy, amino, oxa, carboxy, alkylcarboxy, alkoxy, amido, carbamate, halogen or combinations thereof.

where b=0 to 500, where it is understood that when b is other than 0, bis a distribution having a mode equal to a stated value;

wherein at least one R² comprises a monovalent reactive group, and insome embodiments between one and 3 R² comprise monovalent reactivegroups.

As used herein “monovalent reactive groups” are groups that can undergofree radical and/or cationic polymerization. Non-limiting examples offree radical reactive groups include (meth)acrylates, styryls, vinyls,vinyl ethers, substituted or unsubstituted C₁₋₆alkyl(meth)acrylates,(meth)acrylamides, C₁₋₆alkyl(meth)acrylamides, N-vinyllactams,N-vinylamides, C₂₋₁₂alkenyls, C₂₋₁₂alkenylphenyls,C₂₋₁₂alkenylnaphthyls, C₂₋₆alkenylphenylC₁₋₆alkyls, O-vinylcarbamatesand O-vinylcarbonates. Suitable substituents on said C1-6 alkyls includeethers, hydroxyls, carboxyls, halogens and combinations thereof.Non-limiting examples of cationic reactive groups include vinyl ethersor epoxide groups and mixtures thereof. In one embodiment the freeradical reactive groups comprises (meth)acrylate, acryloxy,(meth)acrylamide, and mixtures thereof.

Suitable monovalent alkyl and aryl groups include unsubstitutedmonovalent C₁ to C₆alkyl groups, and in some embodiments C₁-C₄ alkylgroups, C₆-C₁₄ aryl groups, such as substituted and unsubstitutedmethyl, ethyl, propyl, butyl, 2-hydroxypropyl, propoxypropyl,polyethyleneoxypropyl, combinations thereof and the like.

In one embodiment R² is selected from C₁₋₆alkyl(meth)acrylates, andC₁₋₆alkyl(meth)acrylamides, which may be unsubstituted or substitutedwith hydroxyl, alkylene ether or a combination thereof. In anotherembodiment R² is selected from propyl(meth)acrylates and propyl(meth)acrylamides, wherein said propyl may be optionally substitutedwith hydroxyl, alkylene ether or a combination thereof.

In one embodiment b is zero, one R² is a monovalent reactive group, andat least 3 R¹ are selected from monovalent alkyl groups having one to 16carbon atoms, and in another embodiment from monovalent alkyl groupshaving one to 6 carbon atoms. Non-limiting examples of siliconecomponents of this embodiment include2-methyl-,2-hydroxy-3-[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propoxy]propylester (“SiGMA”),

2-hydroxy-3-methacryloxypropyloxypropyl-tris(trimethylsiloxy)silane,

3-methacryloxypropyltris(trimethylsiloxy)silane (“TRIS”),

3-methacryloxypropylbis(trimethylsiloxy)methyl silane and

3-methacryloxypropylpentamethyldisiloxane.

In another embodiment, b is 2 to 20, 3 to 15 or in some embodiments 3 to10; at least one terminal R² comprises a monovalent reactive group andthe remaining R² are selected from monovalent alkyl groups having 1 to16 carbon atoms, and in another embodiment from monovalent alkyl groupshaving 1 to 6 carbon atoms. In yet another embodiment, b is 3 to 15, oneterminal R² comprises a monovalent reactive group selected fromsubstituted or unsubstituted C₁₋₆alkyl (meth)acrylates, substituted orunsubstituted C₁₋₆alkyl(meth)acrylamides, the other terminal R²comprises a monovalent alkyl group having 1 to 6 carbon atoms and theremaining R² comprise monovalent alkyl group having 1 to 3 carbon atoms.Non-limiting examples of silicone components of this embodiment include(mono-(2-hydroxy-3-methacryloxypropyl)-propyl ether terminatedpolydimethylsiloxane (400-1000 MW)) (“OH-mPDMS”), monomethacryloxypropylterminated mono-n-butyl terminated polydimethylsiloxanes (800-1000 MW),(“mPDMS”), N-(2,3-dihydroxypropane)-N′-(propyltetra(dimethylsiloxy)dimethylbutylsilane)acrylamide methacryamidesilicones of the following formulae (s1) through (s6);

In another embodiment b is 5 to 400 or from 10 to 300, both terminal R¹comprise monovalent reactive groups and the remaining R² areindependently selected from monovalent alkyl groups having 1 to 18carbon atoms which may have ether linkages between carbon atoms and mayfurther comprise halogen.

In another embodiment, one to four R² comprises a vinyl carbonate orcarbamate of the formula:

wherein: Y denotes O—, S— or NH—;

R denotes hydrogen or methyl; and q is 0 or 1.

The silicone-containing vinyl carbonate or vinyl carbamate monomersspecifically include:1,3-bis[4-(vinyloxycarbonyloxy)but-1-yl]tetramethyl-disiloxane;3-(vinyloxycarbonylthio) propyl-[tris(trimethylsiloxy)silane];3-[tris(trimethyl siloxy)silyl]propyl allyl carbamate;3-[tris(trimethylsiloxy)silyl]propyl vinyl carbamate;trimethylsilylethyl vinyl carbonate; trimethylsilylmethyl vinylcarbonate, and

Where biomedical devices with modulus below about 200 are desired, onlyone R² shall comprise a monovalent reactive group and no more than twoof the remaining R² groups will comprise monovalent siloxane groups.

In one embodiment, where a silicone hydrogel lens is desired, the lenswill be made from a reaction mixture comprising at least about 20 weight% and in some embodiments between about 20 and 70% wtsilicone-containing components based on total weight of reactive monomercomponents from which the polymer is made.

Another class of silicone-containing components includes polyurethanemacromers of the following formulae:(*D*A*D*G)_(a)*D*D*E¹;E(*D*G*D*A)_(a)*D*G*D*E¹ or;E(*D*A*D*G)_(a)*D*A*D*E¹   Formulae XII-XIV

wherein:

D denotes an alkyl diradical, an alkyl cycloalkyl diradical, acycloalkyl diradical, an aryl diradical or an alkylaryl diradical having6 to 30 carbon atoms,

G denotes an alkyl diradical, a cycloalkyl diradical, an alkylcycloalkyl diradical, an aryl diradical or an alkylaryl diradical having1 to 40 carbon atoms and which may contain ether, thio or amine linkagesin the main chain;

* denotes a urethane or ureido linkage;

a is at least 1;

A denotes a divalent polymeric radical of Formula:

R¹⁷ independently denotes an alkyl or fluoro-substituted alkyl grouphaving 1 to 10 carbon atoms which may contain ether linkages betweencarbon atoms; v is at least 1; and n provides a moiety weight of 400 to10,000; each of E and E¹ independently denotes a polymerizableunsaturated organic radical represented by formula:

wherein: R¹² is hydrogen or methyl; R¹³ is hydrogen, an alkyl radicalhaving 1 to 6 carbon atoms, or a —CO—Y—R¹¹ radical wherein Y is —O—, —S—or —NH—; R¹¹ is a C₁₋₆ monovalent alkyl, and in some embodiments anunsubstituted C₁₋₃ alkyl; R¹⁴ is a divalent radical having 1 to 12carbon atoms; X denotes —CO— or —OCO—; Z denotes —O— or —NH—; Ar denotesan aromatic radical having 6 to 30 carbon atoms; w is 0 to 6; x is 0 or1; y is 0 or 1; and z is 0 or 1.

In one embodiment the silicone-containing component comprises apolyurethane macromer represented by the following formula:

wherein R¹⁶ is a diradical of a diisocyanate after removal of theisocyanate group, such as the diradical of isophorone diisocyanate; a is1-5, d is 3-4 and c is 10-200 or 10-100. Another suitable siliconecontaining macromer is compound of formula XVIII (in which f+g is anumber in the range of 10 to 30 and h is a number in the range of 20-30,22-26 or 25) formed by the reaction of fluoroether, hydroxy-terminatedpolydimethylsiloxane, isophorone diisocyanate andisocyanatoethylmethacrylate.

Other silicone-containing components suitable for use include thosedescribed is WO 96/31792 such as macromers containing polysiloxane,polyalkylene ether, diisocyanate, polyfluorinated hydrocarbon,polyfluorinated ether and polysaccharide groups. Another class ofsuitable silicone-containing components includes silicone containingmacromers made via GTP, such as those disclosed in U.S. Pat. Nos.5,314,960; 5,331,067; 5,244,981; 5,371,147; and 6,367,929. U.S. Pat.Nos. 5,321,108; 5,387,662; and 5,539,016 describe polysiloxanes with apolar fluorinated graft or side group having a hydrogen atom attached toa terminal difluoro-substituted carbon atom. US 2002/0016383 describeshydrophilic siloxanyl methacrylates containing ether and siloxanyllinkages and crosslinkable monomers containing polyether andpolysiloxanyl groups. Any of the foregoing polysiloxanes can also beused as the silicone-containing component.

In one embodiment of the present invention where a modulus of less thanabout 120 psi is desired, the majority of the mass fraction of thesilicone-containing components used in the lens formulation shouldcontain only one polymerizable functional group (“monofunctionalsilicone containing component”). In this embodiment, to insure thedesired balance of oxygen transmissibility and modulus it is preferredthat all components having more than one polymerizable functional group(“multifunctional components”) make up no more than 10 mmol/100 g of thereactive components, and preferably no more than 7 mmol/100 g of thereactive components.

In another embodiment, the reaction mixtures are substantially free ofsilicone containing components which contain trimethylsiloxy groups.

The silicone containing components may be present in amounts up to about85 weight %, and in some embodiments between about 10 and about 80 andin other embodiments between about 20 and about 70 weight %, based uponall reactive components.

Hydrophilic components include those which are capable of providing atleast about 20% and in some embodiments at least about 25% water contentto the resulting lens when combined with the remaining reactivecomponents. Suitable hydrophilic components include hydrophilicmonomers, prepolymers and polymers and may be present in amounts betweenabout 10 to about 60 weight % based upon the weight of all reactivecomponents, in some embodiments about 15 to about 50 weight %, and inother embodiments between about 20 to about 40 weight %. The hydrophilicmonomers that may be used to make the polymers have at least onepolymerizable double bond and at least one hydrophilic functional group.Examples of polymerizable double bonds include acrylic, methacrylic,acrylamido, methacrylamido, fumaric, maleic, styryl, isopropenylphenyl,O-vinylcarbonate, O-vinylcarbamate, allylic, O-vinylacetyl andN-vinyllactam and N-vinylamido double bonds. Such hydrophilic monomersmay themselves be used as crosslinking agents. “Acrylic-type” or“acrylic-containing” monomers are those monomers containing the acrylicgroup

wherein R is H or CH₃, R⁴ is H, C₁₋₃ unsubstituted alkyl or carbonyl,and Q is O or N, which are also known to polymerize readily, such asN,N-dimethylacrylamide (DMA), 2-hydroxyethyl (meth)acrylate, glycerolmethacrylate, 2-hydroxyethyl methacrylamide, polyethyleneglycolmonomethacrylate, methacrylic acid, acrylic acid, mixtures thereof andthe like.

Hydrophilic vinyl-containing monomers which may be incorporated into thehydrogels include monomers such as N-vinyl lactams (e.g. N-vinylpyrrolidone (NVP)), N-vinyl-2-piperidone, N-vinyl-2-caprolactam,N-vinyl-3-methyl-2-caprolactam, N-vinyl-3-methyl-2-piperidone,N-vinyl-4-methyl-2-piperidone, N-vinyl-4-methyl-2-caprolactam,N-vinyl-3-ethyl-2-pyrrolidone, N-vinyl-4,5-dimethyl-2-pyrrolidone);N-vinyl-N-methyl acetamide, N-vinyl-N-ethyl acetamide, N-vinyl-N-ethylformamide, N-vinyl formamide, N-2-hydroxyethyl vinyl carbamate,N-carboxy-β-alanine N-vinyl ester, vinylimidazole, with NVP beingpreferred in one embodiment.

Additional hydrophilic monomers which may be used include acrylamide,N,N-bis(2-hydroxyethyl)acrylamide, acrylonitrile, N-isopropylacrylamide, vinyl acetate, (meth)acrylic acid, polyethylene glycol(meth)acrylates, 2-ethyl oxazoline, N-(2-hydroxypropyl)(meth)acrylamide, N-(2-hydroxyethyl) (meth)acrylamide,2-methacryloyloxyethyl phosphorylcholine,3-(dimethyl(4-vinylbenzyl)ammonio)propane-1-sulfonate (DMVBAPS),3-((3-acrylamidopropyl)dimethylammonio)propane-1-sulfonate (AMPDAPS),3-((3-methacrylamidopropyl)dimethylammonio)propane-1-sulfonate(MAMPDAPS),3-((3-(acryloyloxy)propyl)dimethylammonio)propane-1-sulfonate (APDAPS),methacryloyloxy)propyl)dimethylammonio)propane-1-sulfonate (MAPDAPS),N-vinyl-N-methylacetamide, N-vinylacetamide,N-vinyl-N-methylpropionamide, N-vinyl-N-methyl-2-methylpropionamide,N-vinyl-2-methylpropionamide, N-vinyl-N,N′-dimethylurea, and the like,and mixtures thereof. In one embodiment suitable hydrophilic monomerscomprise N-vinyl pyrrolidone, N-vinyl-N-methylacetamide,2-methacryloyloxyethyl phosphorylcholine, (meth)acrylic acid,N,N-dimethylacrylamide, N-hydroxypropyl methacrylamide, mono-glycerolmethacrylate, 2-hydroxyethyl acrylamide, bishydroxyethyl acrylamide, and2,3-dihydroxypropyl (meth)acrylamide and the like and mixtures thereof.

In some embodiments the hydrophilic monomers may also comprise chargedmonomers including but not limited to methacrylic acid, acrylic acid,3-acrylamidopropionic acid (ACA1), 4-acrylamidobutanoic acid,5-acrylamidopentanoic acid (ACA2), 3-acrylamido-3-methylbutanoic acid(AMBA), N-vinyloxycarbonyl-α-alanine, N-vinyloxycarbonyl-β-alanine(VINAL), 2-vinyl-4,4-dimethyl-2-oxazolin-5-one (VDMO), reactivesulfonate salts, including, sodium-2-(acrylamido)-2-methylpropanesulphonate (AMPS), 3-sulphopropyl (meth)acrylate potassium salt,3-sulphopropyl (meth)acrylate sodium salt, bis 3-sulphopropyl itaconatedi sodium, bis 3-sulphopropyl itaconate di potassium, vinyl sulphonatesodium salt, vinyl sulphonate salt, styrene sulfonate, sulfoethylmethacrylate, combinations thereof and the like.

Other hydrophilic monomers that can be employed include polyoxyethylenepolyols having one or more of the terminal hydroxyl groups replaced witha functional group containing a polymerizable double bond. Examplesinclude polyethylene glycol with one or more of the terminal hydroxylgroups replaced with a functional group containing a polymerizabledouble bond. Examples include polyethylene glycol reacted with one ormore molar equivalents of an end-capping group such as isocyanatoethylmethacrylate (“TEM”), methacrylic anhydride, methacryloyl chloride,vinylbenzoyl chloride, or the like, to produce a polyethylene polyolhaving one or more terminal polymerizable olefinic groups bonded to thepolyethylene polyol through linking moieties such as carbamate or estergroups.

Still further examples are the hydrophilic vinyl carbonate or vinylcarbamate monomers disclosed in U.S. Pat. No. 5,070,215, and thehydrophilic oxazolone monomers disclosed in U.S. Pat. No. 4,190,277.Other suitable hydrophilic monomers will be apparent to one skilled inthe art.

In one embodiment the hydrophilic monomers which may be incorporatedinto the polymers disclosed herein include hydrophilic monomers such asN,N-dimethyl acrylamide (DMA), 2-hydroxyethyl acrylate, glycerolmethacrylate, 2-hydroxyethyl methacrylamide, N-vinylpyrrolidone (NVP),N-vinyl methacrylamide, HEMA, and polyethyleneglycol monomethacrylate.

In another embodiment the hydrophilic monomers include DMA, NVP, HEMAand mixtures thereof.

The reactive mixtures used to form substrates such as contact lenses mayalso comprise as hydrophilic components one or more polymeric wettingagents. The polymeric wetting agents may comprise one or more of thewater soluble, crosslinked polymers disclosed herein, previouslydisclosed wetting agents or a combination thereof. As used herein, suchpolymeric wetting agents used in reaction mixtures refers to substanceshaving a weight average molecular weight of no less than about 5,000Daltons, wherein said substances upon incorporation to silicone hydrogelformulations, increase the wettability of the cured silicone hydrogels.In one embodiment the weight average molecular weight of these polymericwetting agents is greater than about 30,000; in another between about150,000 to about 2,000,000 Daltons, in yet another between about 300,000to about 1,800,000 Daltons, and in yet another about 500,000 to about1,500,000 Daltons.

Alternatively, the molecular weight of polymeric wetting agents can bealso expressed by the K-value, based on kinematic viscositymeasurements, as described in Encyclopedia of Polymer Science andEngineering, N-Vinyl Amide Polymers, Second edition, Vol. 17, pgs.198-257, John Wiley & Sons Inc. When expressed in this manner,hydrophilic monomers having K-values of greater than about 46 and in oneembodiment between about 46 and about 150. Suitable amounts of polymericwetting agents in reaction mixtures include from about 1 to about 20weight percent, in some embodiments about 5 to about 20 percent, inother embodiments about 6 to about 17 percent, all based upon the totalof all reactive components.

Examples of polymeric wetting agents include but are not limited topolyamides, polylactones, polyimides, polylactams and functionalizedpolyamides, polylactones, polyimides, polylactams, such as DMAfunctionalized by copolymerizing DMA with a lesser molar amount of ahydroxyl-functional monomer such as HEMA, and then reacting the hydroxylgroups of the resulting copolymer with materials containing radicalpolymerizable groups, such as isocyanatoethylmethacrylate ormethacryloyl chloride. Polymeric wetting agents made from DMA or N-vinylpyrrolidone with glycidyl methacrylate may also be used. The glycidylmethacrylate ring can be opened to give a diol which may be used inconjunction with other hydrophilic prepolymer in a mixed system toincrease the compatibility of the component in the reactive mixture. Inone embodiment the polymeric wetting agents contain at least one cyclicmoiety in their backbone, such as but not limited to, a cyclic amide orcyclic imide. Polymeric wetting agents include but are not limited topoly-N-vinyl pyrrolidone, poly-N-vinyl-2-piperidone,poly-N-vinyl-2-caprolactam, poly-N-vinyl-3-methyl-2-caprolactam,poly-N-vinyl-3-methyl-2-piperidone, poly-N-vinyl-4-methyl-2-piperidone,poly-N-vinyl-4-methyl-2-caprolactam, poly-N-vinyl-3-ethyl-2-pyrrolidone,and poly-N-vinyl-4,5-dimethyl-2-pyrrolidone, polyvinylimidazole,poly-N—N-dimethylacrylamide, polyvinyl alcohol, polyacrylic acid,polyethylene-oxide, poly-2-ethyl-oxazoline, heparin polysaccharides,polysaccharides, mixtures and copolymers (including block or random,branched, multichain, comb-shaped or star shaped) thereof, wherepoly-N-vinylpyrrolidone (PVP) is particularly preferred in oneembodiment. Copolymers might also be used such as graft copolymers ofPVP.

The polymeric wetting agents used in reaction mixtures also provideimproved wettability, and particularly improved in vivo wettability tothe medical devices. Without being bound by any theory, it is believedthat the polymeric wetting agents are hydrogen bond receivers which inaqueous environments, hydrogen bond to water, thus becoming effectivelymore hydrophilic. The absence of water facilitates the incorporation ofthe polymeric wetting agents in the reaction mixture. Aside from thespecifically named polymeric wetting agents, it is expected that anypolymer will be useful provided that when said polymer is added to aformulation, the polymer (a) does not substantially phase separate fromthe reaction mixture and (b) imparts wettability to the resulting curedpolymer network. In some embodiments it is preferred that the polymericwetting agents be soluble in the diluent at reaction temperatures.

Compatibilizing agents may also be used. In some embodiments thecompatibilizing component may be any functionalized silicone containingmonomer, macromer or prepolymer which, when polymerized and/or formedinto a final article is compatible with the selected hydrophiliccomponents. The compatibility test disclosed in WO03/022321 may be usedto select suitable compatibilizing agents. In some embodiments, asilicone monomer, prepolymer or macromer which also comprises hydroxylgroups is included in the reaction mixture. Examples include3-methacryloxy-2-hydroxypropyloxy)propylbis(trimethylsiloxy)methylsilane,mono-(3-methacryloxy-2-hydroxypropyloxy)propyl terminated, mono-butylterminated polydimethylsiloxane (MW 1100), hydroxyl functionalizedsilicone containing GTP macromers, hydroxyl functionalized macromerscomprising polydimethyl siloxanes, combinations thereof and the like. Inanother embodiment, the polymeric wettings may be used ascompatibilizing components.

The hydroxyl containing component may also act as a cross-linking agentduring the formation of substrates such as contact lenses.

With respect to making substrates such as contact lenses, it isgenerally necessary to add one or more cross-linking agents, alsoreferred to as cross-linking monomers, to the reaction mixture, such asethylene glycol dimethacrylate (“EGDMA”), trimethylolpropanetrimethacrylate (“TMPTMA”), glycerol trimethacrylate, polyethyleneglycol dimethacrylate (wherein the polyethylene glycol preferably has amolecular weight up to, e.g., about 5000), and other poly(meth)acrylateesters, such as the end-capped polyoxyethylene polyols described abovecontaining two or more terminal methacrylate moieties. The cross-linkingagents are used in the usual amounts, e.g., from about 0.000415 to about0.0156 mole per 100 grams of reactive components in the reactionmixture. Alternatively, if the hydrophilic monomers and/or the siliconecontaining monomers act as the cross-linking agent, the addition of acrosslinking agent to the reaction mixture is optional. Examples ofhydrophilic monomers which can act as the crosslinking agent and whenpresent do not require the addition of an additional crosslinking agentto the reaction mixture include polyoxyethylene polyols described abovecontaining two or more terminal methacrylate moieties.

An example of a silicone containing monomer which can act as acrosslinking agent and, when present, does not require the addition of acrosslinking monomer to the reaction mixture includesα,ω-bismethacryloypropyl polydimethylsiloxane.

The reaction mixture may contain additional components such as, but notlimited to, UV absorbers, photochromic compounds, pharmaceutical andnutriceutical compounds, antimicrobial compounds, reactive tints,pigments, copolymerizable and non-polymerizable dyes, release agents andcombinations thereof.

Generally the reactive components are mixed in a diluent to form areaction mixture. Suitable diluents are known in the art. For siliconehydrogels suitable diluents are disclosed in WO 03/022321, U.S. Pat. No.6,020,445 the disclosure of which is incorporated herein by reference.

Classes of suitable diluents for silicone hydrogel reaction mixturesinclude alcohols having 2 to 20 carbons, amides having 10 to 20 carbonatoms derived from primary amines and carboxylic acids having 8 to 20carbon atoms. In some embodiments primary and tertiary alcohols arepreferred. Preferred classes include alcohols having 5 to 20 carbons andcarboxylic acids having 10 to 20 carbon atoms.

Specific diluents which may be used include 1-ethoxy-2-propanol,diisopropylaminoethanol, isopropanol, 3,7-dimethyl-3-octanol, 1-decanol,1-dodecanol, 1-octanol, 1-pentanol, 2-pentanol, 1-hexanol, 2-hexanol,2-octanol, 3-methyl-3-pentanol, tert-amyl alcohol, tert-butanol,2-butanol, 1-butanol, 2-methyl-2-pentanol, 2-propanol, 1-propanol,ethanol, 2-ethyl-1-butanol,(3-acetoxy-2-hydroxypropyloxy)propylbis(trimethyl siloxy)methylsilane,1-tert-butoxy-2-propanol, 3,3-dimethyl-2-butanol, tert-butoxyethanol,2-octyl-1-dodecanol, decanoic acid, octanoic acid, dodecanoic acid,2-(diisopropylamino)ethanol mixtures thereof and the like.

Preferred diluents include 3,7-dimethyl-3-octanol, 1-dodecanol,1-decanol, 1-octanol, 1-pentanol, 1-hexanol, 2-hexanol, 2-octanol,3-methyl-3-pentanol, 2-pentanol, t-amyl alcohol, tert-butanol,2-butanol, 1-butanol, 2-methyl-2-pentanol, 2-ethyl-1-butanol, ethanol,3,3-dimethyl-2-butanol, 2-octyl-1-dodecanol, decanoic acid, octanoicacid, dodecanoic acid, mixtures thereof and the like.

More preferred diluents include 3,7-dimethyl-3-octanol, 1-dodecanol,1-decanol, 1-octanol, 1-pentanol, 1-hexanol, 2-hexanol, 2-octanol,1-dodecanol, 3-methyl-3-pentanol, 1-pentanol, 2-pentanol, t-amylalcohol, tert-butanol, 2-butanol, 1-butanol, 2-methyl-2-pentanol,2-ethyl-1-butanol, 3,3-dimethyl-2-butanol, 2-octyl-1-dodecanol, mixturesthereof and the like.

Suitable diluents for non-silicone containing reaction mixtures includeglycerin, ethylene glycol, ethanol, methanol, ethyl acetate, methylenechloride, polyethylene glycol, polypropylene glycol, low molecularweight PVP, such as disclosed in U.S. Pat. No. 4,018,853, U.S. Pat. No.4,680,336 and U.S. Pat. No. 5,039,459, including, but not limited toboric acid esters of dihydric alcohols, combinations thereof and thelike.

Mixtures of diluents may be used. The diluents may be used in amounts upto about 55% by weight of the total of all components in the reactionmixture. More preferably the diluent is used in amounts less than about45% and more preferably in amounts between about 15 and about 40% byweight of the total of all components in the reaction mixture.

A polymerization initiator is preferably included in the reactionmixture used to form substrates such as contact lenses. Thepolymerization initiators includes compounds such as lauryl peroxide,benzoyl peroxide, isopropyl percarbonate, azobisisobutyronitrile, andthe like, that generate free radicals at moderately elevatedtemperatures, and photoinitiator systems such as aromatic alpha-hydroxyketones, alkoxyoxybenzoins, acetophenones, acylphosphine oxides,bisacylphosphine oxides, and a tertiary amine plus a diketone, mixturesthereof and the like. Illustrative examples of photoinitiators are1-hydroxycyclohexyl phenyl ketone,2-hydroxy-2-methyl-1-phenyl-propan-1-one,bis(2,6-dimethoxybenzoyl)-2,4-4-trimethylpentyl phosphine oxide(DMBAPO), bis(2,4,6-trimethylbenzoyl)-phenyl phosphineoxide (Irgacure819), 2,4,6-trimethylbenzyldiphenyl phosphine oxide and2,4,6-trimethylbenzoyl diphenylphosphine oxide, benzoin methyl ester anda combination of camphorquinone and ethyl 4-(N,N-dimethylamino)benzoate.Commercially available visible light initiator systems include Irgacure819, Irgacure 1700, Irgacure 1800, Irgacure 819, Irgacure 1850 (all fromCiba Specialty Chemicals) and Lucirin TPO initiator (available fromBASF). Commercially available UV photoinitiators include Darocur 1173and Darocur 2959 (Ciba Specialty Chemicals). These and otherphotoinitiators which may be used are disclosed in Volume III,Photoinitiators for Free Radical Cationic & Anionic Photopolymerization,2nd Edition by J. V. Crivello & K. Dietliker; edited by G. Bradley; JohnWiley and Sons; New York; 1998, which is incorporated herein byreference. The initiator is used in the reaction mixture in effectiveamounts to initiate photopolymerization of the reaction mixture, e.g.,from about 0.1 to about 2 parts by weight per 100 parts of reactivemonomer. Polymerization of the reaction mixture can be initiated usingthe appropriate choice of heat or visible or ultraviolet light or othermeans depending on the polymerization initiator used. Alternatively,initiation can be conducted without a photoinitiator using, for example,e-beam. However, when a photoinitiator is used, the preferred initiatorsare bisacylphosphine oxides, such as bis(2,4,6-trimethylbenzoyl)-phenylphosphine oxide (Irgacure 819®) or a combination of 1-hydroxycyclohexylphenyl ketone and bis(2,6-dimethoxybenzoyl)-2,4-4-trimethylpentylphosphine oxide (DMBAPO), and the preferred method of polymerizationinitiation is visible light. The most preferred isbis(2,4,6-trimethylbenzoyl)-phenyl phosphine oxide (Irgacure 819®).

The preferred range of silicone-containing monomer present in thereaction mixture is from about 5 to 95 weight percent, more preferablyabout 30 to 85 weight percent, and most preferably about 45 to 75 weightpercent of the reactive components in the reaction mixture. Thepreferred range of hydrophilic monomer present is from about 5 to 80weight percent, more preferably about 10 to 60 weight percent, and mostpreferably about 20 to 50 weight percent of the reactive components inthe reaction mixture. The preferred range of diluent present is fromabout 2 to 70 weight percent, more preferably about 5 to 50 weightpercent, and most preferably about 15 to 40 weight percent of the totalreaction mixture (including reactive and nonreactive components).

The reaction mixtures can be formed by any of the methods known to thoseskilled in the art, such as shaking or stirring, and used to formpolymeric articles or devices by known methods.

For example, the biomedical devices may be prepared by mixing reactivecomponents and the diluent(s) with a polymerization initiator and curingby appropriate conditions to form a product that can be subsequentlyformed into the appropriate shape by lathing, cutting and the like.Alternatively, the reaction mixture may be placed in a mold andsubsequently cured into the appropriate article.

Various processes are known for processing the reaction mixture in theproduction of contact lenses, including spincasting and static casting.Spincasting methods are disclosed in U.S. Pat. Nos. 3,408,429 and3,660,545; and static casting methods are disclosed in U.S. Pat. Nos.4,113,224 and 4,197,266. The preferred method for producing contactlenses is by the molding of the silicone hydrogels, which is economical,and enables precise control over the final shape of the hydrated lens.For this method, the reaction mixture is placed in a mold having theshape of the final desired silicone hydrogel, i.e., water-swollenpolymer, and the reaction mixture is subjected to conditions whereby themonomers polymerize, to thereby produce a polymer/diluent mixture in theshape of the final desired product. Then, this polymer/diluent mixtureis treated with a solvent to remove the diluent and ultimately replaceit with water, producing a silicone hydrogel having a final size andshape which are quite similar to the size and shape of the originalmolded polymer/diluent article. This method can be used to form contactlenses and is further described in U.S. Pat. Nos. 4,495,313; 4,680,336;4,889,664; and 5,039,459, incorporated herein by reference.

Biomedical devices, and particularly ophthalmic lenses, have a balanceof properties which makes them particularly useful. Such propertiesinclude clarity, water content, oxygen permeability and contact angle.The incorporation of at least one WSC polymer according to embodimentsof the present invention provides articles having very desirablewettability/contact angles with solutions and improved biometricperformance as evidenced by reduced lipocalin, lipid and mucin uptakelevels. Silicone hydrogel contact lenses incorporating the WSC polymerswill display contact angles of less than about 60° and in someembodiments less than about 40°, and decreases in contact angle of 40%and in some embodiments 50% or more. Lipid uptake can be lowered by 50%or more and silicone hydrogel lenses having about 12 μg, 10 μg, or even5 μg or less may be produced. In one embodiment, the biomedical devicesare contact lenses having a water content of greater than about 17%,preferably greater than about 20% and more preferably greater than about25%.

Suitable oxygen permeabilities for silicone containing lenses arepreferably greater than about 40 barrer and more preferably greater thanabout 60 barrer.

In some embodiments the articles of the present invention havecombinations of the above described oxygen permeability, water contentand contact angle. All combinations of the above ranges are deemed to bewithin the present invention.

The non-limiting examples below further describe this invention.

Wettability of lenses can be determined using a sessile drop techniquemeasured using KRUSS DSA-100™ instrument at room temperature and usingDI water as probe solution. The lenses to be tested (3-5/sample) wererinsed in DI water to remove carry over from packing solution. Each testlens was placed on blotting lint free wipes which were dampened withpacking solution. Both sides of the lens were contacted with the wipe toremove surface water without drying the lens. To ensure properflattening, lenses were placed “bowl side down” on the convex surface oncontact lens plastic moulds. The plastic mould and the lens were placedin the sessile drop instrument holder, ensuring proper central syringealignment and that the syringe corresponds to the assigned liquid. A 3to 4 microliter of DI water drop was formed on the syringe tip using DSA100-Drop Shape Analysis software ensuring the liquid drop was hangingaway from the lens. The drop was released smoothly on the lens surfaceby moving the needle down. The needle was withdrawn away immediatelyafter dispensing the drop. The liquid drop was allowed to equilibrate onthe lens for 5 to 10 seconds and the contact angle was computed based onthe contact angle measured between the drop image and the lens surface.

The water content may be measured as follows: lenses to be tested wereallowed to sit in packing solution for 24 hours. Each of three test lenswere removed from packing solution using a sponge tipped swab and placedon blotting wipes which have been dampened with packing solution. Bothsides of the lens were contacted with the wipe. Using tweezers, the testlens were placed in a weighing pan and weighed. The two more sets ofsamples were prepared and weighed as above. The pan was weighed threetimes and the average is the wet weight.

The dry weight was measured by placing the sample pans in a vacuum ovenwhich has been preheated to 60° C. for 30 minutes. Vacuum was applieduntil at least 0.4 inches Hg is attained. The vacuum valve and pump wereturned off and the lenses were dried for four hours. The purge valve wasopened and the oven was allowed reach atmospheric pressure. The panswere removed and weighed. The water content was calculated as follows:Wet weight=combined wet weight of pan and lenses−weight of weighing panDry weight=combined dry weight of pan and lens−weight of weighing pan% water content wet weight=(wet weight−dry weight)×100

The average and standard deviation of the water content are calculatedfor the samples are reported.

Oxygen permeability (Dk) may be determined by the polarographic methodgenerally described in ISO 18369-4:2006, but with the followingvariations. The measurement is conducted at an environment containing2.1% oxygen. This environment is created by equipping the test chamberwith nitrogen and air inputs set at the appropriate ratio, for example1800 ml/min of nitrogen and 200 ml/min of air. The t/Dk is calculatedusing the adjusted pO2. Borate buffered saline was used. The darkcurrent was measured by using a pure humidified nitrogen environmentinstead of applying MMA lenses. The lenses were not blotted beforemeasuring. Four lenses with uniform thickness in the measurement areawere stacked instead of using lenses of varied thickness. The L/Dk of 4samples with significantly different thickness values are measured andplotted against the thickness. The inverse of the regressed slope is thepreliminary Dk of the sample. If the preliminary Dk of the sample isless than 90 barrer, then an edge correction of (1+(5.88(CT in cm))) isapplied to the preliminary L/Dk values. If the preliminary Dk of thesample is greater than 90 barrer, then an edge correction of (1+(3.56(CTin cm))) is applied to the preliminary L/Dk values. The edge correctedL/Dk of the 4 samples are plotted against the thickness. The inverse ofthe regressed slope is the Dk of the sample. A curved sensor was used inplace of a flat sensor. The resulting Dk value is reported in barrers.

Lipocalin uptake can be measured using the following solution andmethod. The lipocalin solution contained B Lactoglobulin (Lipocalin)from bovine milk (Sigma, L3908) solubilized at a concentration of 2mg/ml in phosphate saline buffer (Sigma, D8662) supplemented by sodiumbicarbonate at 1.37 g/l and D-Glucose at 0.1 g/l.

Three lenses for each example were tested using the lipocalin solution,and three were tested using PBS as a control solution. The test lenseswere blotted on sterile gauze to remove packing solution and asepticallytransferred, using sterile forceps, into sterile, 24 well cell cultureplates (one lens per well) each well containing 2 ml of lipocalinsolution. Each lens was fully immersed in the solution. Control lenseswere prepared using PBS as soak solution instead of lipocalin. Theplates containing the lenses immersed in lipocalin solution as well asplates containing control lenses immersed in PBS, were parafilmed toprevent evaporation and dehydration, placed onto an orbital shaker andincubated at 35° C., with agitation at 100 rpm for 72 hours. After the72 hour incubation period the lenses were rinsed 3 to 5 times by dippinglenses into three (3) separate vials containing approximately 200 mlvolume of PBS. The lenses were blotted on a paper towel to remove excessPBS solution and transferred into sterile 24 well plates each wellcontaining 1 ml of PBS solution.

Lipocalin uptake can be determined using on-lens bicinchoninic acidmethod using QP-BCA kit (Sigma, QP-BCA) following the proceduredescribed by the manufacturer (the standards prep is described in thekit) and is calculated by subtracting the optical density measured onPBS soaked lenses (background) from the optical density determined onlenses soaked in lipocalin solution. Optical density was measured usinga Synergyll Micro-plate reader capable for reading optical density at562 nm.

Mucin uptake can be measured using the following solution and method.The Mucin solution contained Mucins from bovine submaxillary glands(Sigma, M3895-type 1-S) solubilized at a concentration of 2 mg/ml inphosphate saline buffer (Sigma, D8662) supplemented by sodiumbicarbonate at 1.37 g/l and D-Glucose at 0.1 g/l.

Three lenses for each example were tested using Mucin solution, andthree were tested using PBS as a control solution. The test lenses wereblotted on sterile gauze to remove packing solution and asepticallytransferred, using sterile forceps, into sterile, 24 well cell cultureplates (one lens per well) each well containing 2 ml of Mucin solution.Each lens was fully immersed in the solution. Control lenses wereprepared using PBS as soak solution instead of lipocalin.

The plates containing the lenses immersed in Mucin as well as platescontaining control lenses immersed in PBS were parafilmed to preventevaporation and dehydration, placed onto an orbital shaker and incubatedat 35° C., with agitation at 100 rpm for 72 hours. After the 72 hourincubation period the lenses were rinsed 3 to 5 times by dipping lensesinto three (3) separate vials containing approximately 200 ml volume ofPBS. The lenses were blotted on a paper towel to remove excess PBSsolution and transferred into sterile 24 well plates each wellcontaining 1 ml of PBS solution.

Mucin uptake can be determined using on-lens bicinchoninic acid methodusing QP-BCA kit (Sigma, QP-BCA) following the procedure described bythe manufacturer (the standards prep is described in the kit) and iscalculated by subtracting the optical density measured on PBS soakedlenses (background) from the optical density determined on lenses soakedin Mucin solution. Optical density was measured using a SynergyllMicro-plate reader capable for reading optical density at 562 nm.

Cell viability can be evaluated in vitro using a reconstituted cornealepithelium tissue construct. The tissue construct was a full thicknesscorneal epithelium (corneal epitheliam tissue from Skinethics)reconstituted and grown in vitro on a polycarbonate insert at the airliquid interface to form a fully stratified epithelial construct.

For the evaluation of lenses a punch biopsy (0.5 cm²) of the lens wasapplied topically onto the tissue followed by a 24-hour incubation at37° C., 5% CO₂. The lens biopsy was removed, and tissue was washed withPBS. Cell viability was then measured using the MTT colorimetric assay(Mosman, T. Rapid colorimetric assay for cellular growth and survival:application to proliferation and cytotoxicity assays. J. Immunol.Methods, 65; 55-63 (1983)): tissues were incubated in the presence ofMTT for 3 hours at 37° C., 5% CO₂, followed by extraction of the tissuesin isopropyl alcohol. Absorbance of the isopropyl alcohol extracts wasthen measured at 550 nm using a microplate reader. Results wereexpressed as a percentage of the PBS control (tissues treated with PBSversus lens-treated tissues).

For the evaluation of solutions 30 μg of solution was applied topicallyonto the tissue. The rest of the cell viability was as described forlenses. Each evaluation was done in triplicate.

Lipid uptake was measured as follows:

A standard curve was set up for each lens type under investigation.Tagged cholesterol (cholesterol labeled with NBD([7-nitrobenζ-2-oxa-1,3-diazol-4-yl], CH-NBD; Avanti, Alabaster, Ala.))was solubilized in a stock solution of 1 mg/mL lipid in methanol at 35°C. Aliquots were taken from this stock to make standard curves inphosphate-buffered saline (PBS) at pH 7.4 in a concentration range from0 to 100 micg/mL.

One milliliter of standard at each concentration was placed in the wellof a 24-well cell culture plate. 10 lenses of each type were placed inanother 24-well plate and soaked alongside the standard curve samples in1 mL of a concentration of 20 micg/ml of CH-NBD. Another set of lenses(5 lenses) were soaked in PBS without lipids to correct for anyautofluorescence produced by the lens itself. All concentrations weremade up in phosphate buffered saline (PBS) at pH 7.4. Standard curves,test plates (containing lenses soaked in CH-NBD) and control plates(containing lenses soaked in PBS) were all wrapped in aluminum foil tomaintain darkness and were incubated for 24 hours, with agitation at35.C. After 24 hours the standard curve, test plates and control plateswere removed from the incubator. The standard curve plates wereimmediately read on a micro-plate fluorescence reader (Synergy HT)).

The lenses from the test and control plates were rinsed by dipping eachindividual lens 3 to 5 times in 3 consecutive vials containingapproximately 100 ml of PBS to ensure that only bound lipid would bedetermined without lipids carryover. The lenses were then placed in afresh 24-well plate containing 1 mL of PBS in each well and read on thefluorescence reader. After the test samples were read, the PBS wasremoved, and 1 mL of a fresh solution of CH-NBD were placed on thelenses in the same concentrations as previously mentioned and placedback in the incubator at 35° C., with rocking, until the next period.This procedure was repeated for 15 days until complete saturation oflipids on lenses. Only the lipid amount obtained at saturation wasreported.

Lysozyme uptake can be measured as follows: The lysozyme solution usedfor the lysozyme uptake testing contained lysozyme from chicken eggwhite (Sigma, L7651) solubilized at a concentration of 2 mg/ml inphosphate saline buffer supplemented by Sodium bicarbonate at 1.37 g/land D-Glucose at 0.1 g/l.

The lipocalin solution contained B Lactoglobulin (Lipocalin) from bovinemilk (Sigma, L3908) solubilized at a concentration of 2 mg/ml inphosphate saline buffer supplemented by Sodium bicarbonate at 1.37 g/land D-Glucose at 0.1 g/l.

Three lenses for each example were tested using each protein solution,and three were tested using PBS as a control solution. The test lenseswere blotted on sterile gauze to remove packing solution and asepticallytransferred, using sterile forceps, into sterile, 24 well cell cultureplates (one lens per well) each well containing 2 ml of lysozymesolution. Each lens was fully immersed in the solution. 2 ml of thelysozyme solution was placed in a well without a contact lens as acontrol.

The plates containing the lenses and the control plates containing onlyprotein solution and the lenses in the PBS, were parafilmed to preventevaporation and dehydration, placed onto an orbital shaker and incubatedat 35° C., with agitation at 100 rpm for 72 hours. After the 72 hourincubation period the lenses were rinsed 3 to 5 times by dipping lensesinto three (3) separate vials containing approximately 200 ml volume ofPBS. The lenses were blotted on a paper towel to remove excess PBSsolution and transferred into sterile conical tubes (1 lens per tube),each tube containing a volume of PBS determined based upon an estimateof lysozyme uptake expected based upon on each lens composition. Thelysozyme concentration in each tube to be tested needs to be within thealbumin standards range as described by the manufacturer (0.05 microgramto 30 micrograms). Samples known to uptake a level of lysozyme lowerthan 100 μg per lens were diluted 5 times. Samples known to uptakelevels of lysozyme higher than 500 μg per lens (such as etafilcon Alenses) are diluted 20 times.

1 ml aliquot of PBS was used for all samples other than etafilcon. 20 mlwere used for etafilcon A lens. Each control lens was identicallyprocessed, except that the well plates contained PBS instead of eitherlysozyme or lipocalin solution.

Lysozyme and lipocalin uptake was determined using on-lens bicinchoninicacid method using QP-BCA kit (Sigma, QP-BCA) following the proceduredescribed by the manufacturer (the standards prep is described in thekit) and is calculated by subtracting the optical density measured onPBS soaked lenses (background) from the optical density determined onlenses soaked in lysozyme solution.

Optical density can be measured using a Synergyll Micro-plate readercapable for reading optical density at 562 nm.

The following abbreviations will be used throughout the Preparations andExamples and have the following meanings.

ACA1 3-acrylamidopropionic acid;

ACA2 5-acrylamidopentanoic acid;

AIBN 2,2′-azobisisobutyronitrile (Sigma-Aldrich)

4-BBB 4-(bromomethyl)benzoyl bromide (Sigma-Aldrich);

DMA N,N-dimethylacrylamide (Jarchem)

Irgacure-819 bis(2,4,6-trimethylbenzoyl)-phenylphosphineoxide (CibaSpecialty Chemicals);

KX potassium O-ethyl xanthogenate;

mPDMS monomethacryloxypropyl terminated mono-n-butyl terminatedpolydimethylsiloxane (800-1000 MW);

NaHTTC sodium hexyltrithiocarbonate;

HBTTC S-hexyl-S′-benzyl-trithiocarbonate, prepared in Preparation 4

MBA N,N′-methylenebisacrylamide (Sigma Aldrich)

MBMA N,N′-methylene bismethacrylamide (TCI)

NVP N-vinylpyrrolidone (Acros Chemical), further purified via vacuumdistillation;

HO-mPDMS mono-(2-hydroxy-3-methacryloxypropyl)-propyl ether terminatedpolydimethylsiloxane (400-1000 MW));

SiGMA2-methyl-,2-hydroxy-3-[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propoxy]propylester;

TRIS-VC tris(trimethylsiloxy)silylpropyl vinyl carbamate;

V₂D₂₅ a silicone-containing vinyl carbonate describe at col. 4, lines33-42 of U.S. Pat. No. 5,260,000

D3O 3,7-dimethyl-3-octanol

HPMA N-(2-hydroxypropyl) methacrylamide (Polysciences, Inc.)

(VA-044) 2,2′-azobis[2-(2-imidazoliN-2-yl)propane]dihydrochloride, WakoSpecialty Chemicals

DPBS Dulbecco's Phosphate Buffered Saline 1× (Cellgro)

Borate buffer is an ophthalmic solution containing the followingcomponents

Component Wt % Deionized Water 98.48 Sodium Chloride 0.44 Boric Acid0.89 Sodium Borate Decahydrate 0.17 Ethylenediamine 0.01 Tetraacetate(EDTA)

Preparation 1. Synthesis of poly(N-(2-hydroxypropyl methacrylamide)(PHPMA) Nanogel via RAFT Polymerization

HPMA was dissolved in hot acetonitrile, filtered and precipitated. TheCTA, 4-cyano-4-(ethyltrithiocarbonate)pentanoic acid (ETP), was obtainedfrom Poly Sciences and used as received. MBMA, VA-044, and Dulbecco'sPhosphate Buffered Saline were used as received, in the amounts listedin Table, 1.

TABLE 1 Materials Amount HPMA 100 g MBMA 850 mg ETP 615 mg VA-044 2.25 gDPBS 200 g

The polymerization solution was prepared by adding HPMA, CTA, MBMA andbuffer to a 500 mL round-bottom three neck flask. The flask wasconnected to a mechanical stirrer and closed to the atmosphere, andnitrogen was bubbled through the monomer mix. A heating mantle wasplaced under the flask and it was warmed to 50° C. VA-044 was weighed ina 20 mL vial and dissolved in 8 g of DPBS to form an initiator solution.It was purged of O₂ with N₂ in an N₂ atmosphere for 30 minutes. Afterone hour of stirring and heating the monomer mix was completelydissolved and degassed. The initiator solution was then added to themonomer mix via syringe.

The polymerization solution was cured under an N₂ atmosphere at 50° C.for 180 minutes with continuous stirring. The temperature was monitoredto make sure it did not rise above 54° C. The heating mantle was removedwhen necessary to reduce heat.

After curing, the resulting solid polymerized material was addeddrop-wise to vigorously stirring acetone to precipitate the product. A 2L flask filled with 1600 mL of acetone was used. The precipitatedpolymer was dried in vacuo for several hours. It was further purifiedvia tangential flow filtration. The polymer was analyzed for MW and MWDvia SEC-MALLS.

Preparation 2. Synthesis of poly(N,N-dimethylacrylamide) (PDMA) Nanogelvia RAFT Polymerization

Materials:

DMA was further purified via vacuum distillation. The CTA,S-benzyl-S′-hexyl-trithiocarbonate (HBTTC) was prepared according toPreparation 4. The MBA, and AIBN were used as received, in the amountsshown in Table 2.

TABLE 2 Materials Amount DMA 125.0 g HBTTC 3.59 g AIBN 104 mg MBA 2.46 g1-Propanol 125.0 g

125 g of DMA and 1-propanol were weighed in a 500 mL three-neck flask.Next, HBTTC and MBA were added, and the solution was purged with N₂ forone hour to remove O₂ while stirring with a mechanical stirrer. AIBN(CTA to initiator ratio=20) was weighed into a vial and dissolved in 5 gof 1-propanol. It was then purged with N₂ in an N₂ atmosphere for onehour to remove O₂ from the solution.

The solution was heated to 60° C., and the initiator solution wasinjected into the monomer solution. The temperature of the reactionmixture was monitored throughout the polymerization. It was neverallowed to rise above 70° C. A water bath was used to cool the flaskwhen necessary. The total reaction time was 210 minutes. The reactionmixture was quenched by exposing it to air and bubbling air through it.

After curing, the polymer was added drop-wise to vigorously stirringdiethyl ether to precipitate the product. A 2 L flask containing 1600 mLether was used. The precipitated polymer was dried in vacuo for severalhours. It was further purified via Soxhlet extraction in hexanes for sixdays. The polymer was analyzed for MW and MWD via SEC-MALLS.

Preparation 3. Synthesis of Linear PHPMA Homopolymer

The HPMA and V-501 were used as received.

650 g of HPMA and 4875 g DI water were added to a 12 L flask equippedwith a sparge tube, overhead stirrer, and temperature probe. Theresulting solution was sparged with N₂ and stirred at 250 rpm for twohours while allowing the solution temperature to reach 65° C.

Once the reaction at reached 65° C., 0.85 g V-501 was added and thesolution temperature was raised to 70° C. and held at that temperaturefor 24 hours. The heat was removed and the reaction was allowed to coolto 40° C.

The resulting polymer solution was divided into 600 mL portions and eachportion was precipitated from 2 L of acetone. The isolated solid polymerwas filtered and dried overnight in a hood, then broken up and driedover 24-48 hours. Because the polymer was still wet, it was placed in aWaring blender with 2 L of acetone (in 5 portions) and blended for 2minutes to remove additional water. The solid ground polymer was onceagain isolated and dried for 24-48 hours at 50-55 degrees C. The polymerwas then dissolved in 4500 g of methanol and precipitated (portion-wise)from acetone in a Waring blender. The high shear precipitate resulted ina fine powder which was easily isolated via filtration and dried to aconstant weight over 48 hours. The final polymer yield was 84.9%. Thepolymer was analyzed for MW and MWD via SEC-MALLS.

Preparation 4. Synthesis of S-hexyl-S′benzyl-trithiocarbonate (HBTTC)

Sodium in kerosene (Sigma Aldrich) was added in pieces slowly undernitrogen to 20 mL of methanol to form sodium methoxide. The resultingsolution was added to a flask containing 1-hexanethiol (Sigma Aldrich)in several aliquots. Carbon disulfide (Sigma Aldrich) was addeddrop-wise via syringe. The solution turned yellow immediately. Thesolution was allowed to react for 15 minutes. Benzyl bromide (SigmaAldrich) was then added dropwise via syringe. A precipitate formedimmediately. The reaction was allowed to proceed for two hours. A yellowoil eventually formed at the bottom of the flask. The methanol wasroto-vapped off and the product was separated from the sodium salt withdeionized water and hexane. The aqueous layer was approximately 50 mLand was extracted three times with 50 mL of hexane. The hexane wascombined, dried over Na₂SO₄ and reduced to dryness via rotaryevaporation. ¹H NMR (300 MHz, CDCl₃): δ (ppm) 0.875-1.125 (t, 3H),1.25-1.63 (m, 6H), 1.63-1.95 (m, 2H), 3.25-3.63 (t, 2H), 4.63-4.8 (s,2H), 7.25-7.5 (m, 5H).

Examples 1-2 and Comparative Examples 1 and 2

Senofilcon A lenses were removed from their packages and transferred toglass vials containing 3 mL of BBPS (Comparative Example 1); 3 mL ofBBPS containing 5000 ppm of the WSC polymers formed in Preparations 1-2(Examples 1 and 2, respectively), or 3 mL of BBPS and the linear polymerof Preparation 3 (Comparative Example 2). The lenses were capped andcrimp-sealed and subsequently sterilized at 124° C. for 30 minutes. Thefollowing biometrics data was obtained for lenses treated with each ofthe polymers, and for untreated senofilcon A lenses (Comparative Example1). The results are shown in Table 4, below.

TABLE 4 Property CE 1 Ex 1 Ex 2 CE 2 Polymer N/A WSC WSC Linear PHPMAPDMA HPMA Lipid Uptake (μg/lens) 31.89 6 6 17.2 Sessile Drop 48.3°44.03° 40.35° 51.6° CoF 1.0 1.67 0.84 2.05 Mucin (μg/lens) 5.23 2.252.94 3.23 Lipocalin (μg/lens) 3.32 2.06 1.99 2.4

The WSC polymers of the present invention provide dramatically reducedlipid uptake compared to both the untreated control lens of ComparativeExample 1, and lenses treated with the linear PDMA polymer ofComparative Example 2. Mucin and lipocalin uptake of the lenses of thepresent invention were also reduced compared to the control and thelinear PDMA polymer.

Reference throughout this specification to “one embodiment,” “certainembodiments,” “one or more embodiments” or “an embodiment” means that aparticular feature, structure, material, or characteristic described inconnection with the embodiment is included in at least one embodiment ofthe invention. Thus, the appearances of the phrases such as “in one ormore embodiments,” “in certain embodiments,” “in one embodiment” or “inan embodiment” in various places throughout this specification are notnecessarily referring to the same embodiment of the invention.Furthermore, the particular features, structures, materials, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It will be apparent to those skilled in the art thatvarious modifications and variations can be made to the method andapparatus of the present invention without departing from the spirit andscope of the invention. Thus, it is intended that the present inventioninclude modifications and variations that are within the scope of theappended claims and their equivalents.

What is claimed is:
 1. A process comprising contacting a contact lenswith a solution comprising a lipid uptake reducing amount of at leastone water soluble, crosslinked copolymer under contacting conditionssuitable to associate said copolymer with said contact lens; whereinsaid cross-linked copolymer comprises a plurality of crosslinked primarypolymer chains each having a degree of polymerization in the range ofabout 10 to about 10,000, wherein said cross-linked copolymer does notcomprise repeating units derived from a substituted or unsubstitutedacrylic acid bonded directly to the polymer backbone.
 2. The process ofclaim 1 wherein said contact lens comprises a silicone hydrogel contactlens.
 3. The process of claim 1 wherein said water soluble, cross-linkedcopolymer has a cross-linker to primary polymer chain molar ratio in therange of about 0.01 to about
 3. 4. The process of claim 1 wherein saidlipid uptake reducing amount is at least about 10 ppm.
 5. The process ofclaim 1 wherein said lipid uptake reducing amount is in the range ofabout 10 ppm to about 10,000 ppm.
 6. The process of claim 1 wherein thelipid uptake by the lens is no more than about 10 μg/lens.
 7. Theprocess of claim 1, wherein said primary polymer chains are selectedfrom the group consisting of hydrophilic polymers and copolymers, protondonating polymers and copolymers, proton accepting polymers andcopolymers, ionic polymers and copolymers, complexing polymers andcopolymers, stimuli responsive polymers and copolymers and mixturesthereof.
 8. The process of claim 7, wherein the proton donating polymersand copolymers comprise one or more alcohols.
 9. The process of claim 7,wherein the proton accepting polymers and copolymers comprise one ormore amides.
 10. The process of claim 7, wherein the ionic polymers andcopolymers comprise one or more of the following: a carboxylate, asulfonate, an ammonium salt, and a phosphonium salt.
 11. The process ofclaim 7, wherein the complexing polymers and copolymers comprise one ormore boronic acid functionalities and/or hydroxyl functionalities. 12.The process of claim 7, wherein the stimuli responsive polymers andcopolymers comprise a polymer selected from the group consisting oftemperature-responsive polymers, pH responsive polymers, electrolyteresponsive polymers, light responsive polymers and mixtures thereof. 13.The process of claim 12, wherein the temperature-responsive polymer ispoly(N-isopropylacrylamide).
 14. The process of claim 7 wherein thecopolymers are both hydrophilic and proton donating.
 15. The process ofclaim 14 wherein the copolymers comprise repeating units derived fromthe polymerization of at least one monomer selected from the groupconsisting of N-vinyl pyrrolidone, N,N-dimethyl acrylamide, andN-hydroxypropyl methacrylamide.
 16. The process of claim 1 wherein thecopolymers are formed from monomers selected from the group consistingof vinyl amides, vinyl lactones, vinylimides, vinyl lactams, hydrophilic(meth)acrylates, (meth)acrylamides, and mixtures thereof.
 17. Theprocess of claim 1 wherein said primary polymer chains are cross-linkedby at least one cross-linking agent selected from the group consistingof an N,N′-alkylenebis(meth)acrylamide,polyalkyleneglycoldi(meth)acrylate,polyalkyleneglycoldi(meth)acrylamide, and combinations thereof.
 18. Theprocess of claim 1 wherein said primary polymer chains independentlyhave a degree of polymerization in the range of about 50 to about 5,000.19. The process of claim 1 wherein said primary polymer chainsindependently have a degree of polymerization in the range of about 100to about
 1000. 20. The process of claim 1 wherein said primary polymerchains independently have a degree of polymerization in the range ofabout 100 to about
 500. 21. The process of claim 1 wherein said primarypolymer chains independently have a degree of polymerization in therange of about 100 to about
 300. 22. The process of claim 1 wherein saidcross-linked copolymer has a cross-linker to primary polymer chain molarratio in the range of about 0.01 to about
 3. 23. The process of claim 1wherein said primary polymer chains are cross-linked to other primarypolymer chains of said hydrophilic nanogel having polydispersity indices(PDIs) of less than about 1.5.
 24. The process of claim 22 wherein saidprimary polymer chains are cross-linked by covalent bonding, ionicbonding, hydrogen bonding, or a combination thereof.
 25. The process ofclaim 1 wherein said primary polymer chains, ζ, are represented by theformula

wherein R₁ is a divalent group selected from the group consisting ofoptionally substituted alkylene; optionally substituted saturated,unsaturated or aromatic carbocyclic or heterocyclic rings; optionallysubstituted alkylthio; optionally substituted alkoxy; or optionallysubstituted dialkylamino; U is independently selected from the groupconsisting of hydrogen, halogen, C₁-C₄ alkyl which may be optionallysubstituted with hydroxyl, alkoxy, aryloxy (OR″), carboxy, acyloxy,aroyloxy (O₂CR″), alkoxy-carbonyl, aryloxy-carbonyl (CO₂R″) andcombinations thereof; V is independently selected from the groupconsisting of R″, —CO₂R″, —COR″, —CN, —CONH₂, —CONHR″, —CONR″₂, —O₂CR″,—OR″, cyclic and acyclic N-vinyl amides and combinations thereof; R″ isindependently selected from the group consisting of optionallysubstituted C₁-C₁₈ alkyl, C₂-C₁₈ alkenyl, aryl, heterocyclyl, alkarylwherein the substituents are independently selected from the group thatconsists of epoxy, hydroxyl, alkoxy, acyl, acyloxy, carboxy,carboxylate, sulfonic acid, and sulfonate, alkoxy- or aryloxy-carbonyl,isocyanato, cyano, silyl, halo, dialkylamino; phosphoric acids,phosphates, phosphonic acids, phosphonates and combinations thereof;R₁₅′ and R₁₅ are residues of hydrophilic, free radical reactivecross-linking agents; R₁₈ is a controlled radical polymerization agent;ζ_(i) is another primary chain, are mole fractions, and α is equal toabout 0.85 to about 0.999, β is not 0, and the mole fractions of β and γcombined are about 0.15 to about 0.001.
 26. The process of claim 25wherein said primary polymer chains, ζ, are represented by the formula

Wherein R₁, U, V, R₁₅, R_(15′), α, β, γ and m are as defined in claim25.
 27. The process of claim 25 or 26 wherein R₁ is selected from thegroup consisting of 4-cyanopentanoate, isobutanoic, or a benzylic group.28. The process of claim 25 or 26 wherein R₁ is selected from the groupconsisting of a cyano-methy or cumyl group.
 29. The process of claim 25or 26 wherein R₁ is polyvalent.
 30. The process of claim 25 or 26wherein U is selected from H or methyl.
 31. The process of claim 25 or26 wherein R″ is selected from the group consisting of methyl, —CH₂OH,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂—CO₂ ⁻, —CH₂CH₂—CO₂ ⁻, —CH₂CH₂CH₂—CO₂ ⁻,—CH₂CH₂CH₂CH₂—CO₂ ⁻, —CH₂CH₂CH₂CH₂CH₂—CO₂ ⁻, —CH₂—SO₃ ⁻, —CH₂CH₂—SO₃ ⁻,—CH₂CH₂CH₂—SO₃ ⁻, —CH₂CH₂CH₂CH₂—SO₃ ⁻, —CH₂CH₂CH₂CH₂CH₂—SO₃ ⁻,—(CH₃)₂—CH₂—CO₂ ⁻, —(CH₃)₂—CH₂—SO₃H, —CH₂CH₂CH₂—⁺N(CH₃)₂—CH₂CH₂—CO₂ ⁻,—CH₂CH₂—⁺N(CH₃)₂—CH₂CH₂—CO₂ ⁻, —CH₂CH₂CH₂—⁺N(CH₃)₂—CH₂CH₂CH₂—SO₃ ⁻,—CH₂CH₂—⁺N(CH₃)₂—CH₂CH₂CH₂—SO₃ ⁻, —CH₂CH₂CH₂—⁺N(CH₃)₂—CH₂CH₂CH₂—PO₃ ⁻²,—CH₂CH₂—⁺N(CH₃)₂—CH₂CH₂CH₂—PO₃ ⁻², —CH₂CH₂CH₂—⁺N(CH₃)₂—CH₂CH₂—PO₃⁻²—CH₂CH₂—⁺N(CH₃)₂—CH₂CH₂—PO₃ ⁻², and combinations thereof.
 32. Theprocess of claim 30 wherein V is selected from the group consisting ofpyrrolidonyl, piperidonyl, 2-caprolactam, 3-methyl-2-caprolactam,3-methyl-2-piperidonyl, 4-methyl-2-piperidonyl, 4-methyl-2-caprolactam,3-ethyl-2-pyrrolidonyl, 4,5-dimethyl-2-pyrrolidonyl, imidazolyl,N—N-dimethylamido, amido, N,N-bis(2-hydroxyethyl)amido, -cyano,N-isopropyl amido, acetate, carboxypolyethylene glycol,N-(2-hydroxypropyl)amido, N-(2-hydroxyethyl) amido, carboxyethylphosphorylcholine, 3-(dimethyl(4-benzyl)ammonio)propane-1-sulfonate3-((3-amidopropyl)dimethylammonio)propane-1-sulfonate3-((3-(carboxy)propyl)dimethylammonio)propane-1-sulfonateN-methylacetamide, -acetamide, N-methylpropionamide,N-methyl-2-methylpropionamide, 2-methylpropionamide, N,N′-dimethylurea,and the like, and mixtures thereof.
 33. The process of claim 30 whereinV is selected from the group consisting of —N—(CH₃)₂, pyrrolidonyl,—CON(CH₃)₂, N-(2-hydroxyethyl) amido or —N(CH₃)COCH₃.
 34. The process ofclaim 25 or 26 wherein R₁₅ and R₁₅′ cross-linking agents are free ofdimethylsiloxane groups.
 35. The process of claim 25 or 26 wherein R₁₅and R₁₅′ are polymerization residues of at least one crosslinking agentselected from the group consisting of N,N′-alkylenebis(meth)acrylamides;polyalkyleneglycoldi(meth)acrylates,polyalkyleneglycoldi(meth)acrylamides, triallyl cyanurate,1,3-divinylimidazolidin-2-one, and3,3″alkylenebis(1-vinylpyrrolidin-2-one), wherein the alkylene has 1-12carbons, and mixtures thereof.
 36. The process of claim 25 or 26 whereinR₁₅ and R₁₅′ are polymerization residues of at least one crosslinkingagent selected from the group consisting ofN,N′-methylenebis(meth)acrylamide; N,N′-ethylenebis(meth)acrylamide;N,N′-propylenebis(meth)acrylamide; N,N′-butylenebis(meth)acrylamide;N,N′-pentamethylenebis(meth)acrylamide; N,N′hexamethylenebis(meth)acrylamide; ethylene glycol di(meth)acrylate,triethylene glycol di(meth)acrylate, tetra-ethylene glycoldi(meth)acrylate; N,N′-(oxybis(ethane-2,1-diyl))diacrylamideN,N′-(((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))diacrylamide,triallyl cyanurate, 1,3-divinylimidazolidin-2-one and mixtures thereof.37. The process of claim 25 or 26 wherein R₁₈ is a RAFT or ATRP controlagent.
 38. The process of claim 25 or 26 wherein a is about 0.92 toabout 0.999, and the combined mole fraction of β and γ is about 0.08 toabout 0.001.
 39. The process of claim 25 or 26 wherein a is about 0.95to about 0.999, and the combined mole fraction of β and γ is about 0.05to about 0.001.
 40. The process of claim 25 or 26 wherein a is about0.97 to about 0.999, and the combined mole fraction of β and γ is about0.025 to about 0.001.
 41. The process of claim 25 or 26 wherein saidwater soluble, crosslinked polymer is free of substrate associativeblocks.
 42. The process of claim 25 or 26 wherein at least about 20% ofV are derived from N-(2-hydroxypropyl) (meth)acrylamide.
 43. The processof claim 25 or 26 wherein V comprises repeating units derived fromcomonomers.
 44. The process of claim 25 or 26 wherein V is substantiallyfree of anionic groups.
 45. The process of claim 25 or 26 wherein V isfree of anionic groups.
 46. The process of claim 43 wherein saidcomonomers are selected from the group consisting of hydrophilicmonomers, hydrophobic monomers, anionic monomers, cationic monomers,zwitterionic monomers, stimuli responsive monomers and combinationsthereof.
 47. The process of claim 43 wherein said comonomers areselected from the group consisting of anionic monomers, zwitterionicmonomers and combinations thereof.